New processes

ABSTRACT

The invention relates to a new process for producing NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone. In detail, the new processes, according to the present invention, are ultimately related to the synthesis of intermediates to prepare the above NEP inhibitors, namely compounds according to formula (1), or salt thereof, 
     
       
         
         
             
             
         
       
     
     wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, and R3 is a carboxyl group or an ester group, preferably carboxyl group or alkyl ester.

NEW PROCESSES

The invention relates to a new process for producing NEP inhibitors orprodrugs thereof, in particular NEP inhibitors comprising aγ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone.

Endogenous atrial natriuretic peptides (ANP), also called atrialnatriuretic factors (ANF) have diuretic, natriuretic and vasorelaxantfunctions in mammals. The natural ANF peptides are metabolicallyinactivated, in particular by a degrading enzyme which has beenrecognized to correspond to the enzyme neutral endopeptidase (NEP, EC3.4.24.11), also responsible for e.g. the metabolic inactivation ofenkephalins.

In the art biaryl substituted phosphonic acid derivatives are knownwhich are useful as neutral endopeptidase (NEP) inhibitors, e.g. asinhibitors of the ANF-degrading enzyme in mammals, so as to prolong andpotentiate the diuretic, natriuretic and vasodilator properties of ANFin mammals by inhibiting the degradation thereof to less activemetabolites. NEP inhibitors are thus particularly useful for thetreatment of conditions and disorders responsive to the inhibition ofneutral endopeptidase (EC 3.4.24.11), particularly cardiovasculardisorders such as hypertension, renal insufficiency including edema andsalt retention, pulmonary edema and congestive heart failure.

Processes for preparing NEP-inhibitors are known. U.S. Pat. No.5,217,996 describes biaryl substituted 4-amino-butyric acid amidederivatives which are useful as neutral endopeptidase (NEP) inhibitors,e.g. as inhibitors of the ANF-degrading enzyme in mammals. U.S. Pat. No.5,217,996 discloses the preparation ofN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester. In the preparation of said compoundN-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester is hydrogenated in the presence of palladium oncharcoal. A major drawback of said process is that such a hydrogenationstep is not very selective and yieldsN-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoicacid ethyl ester as a 80:20 mixture of diastereomers. Moreover, theprocess for preparingN-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-(2)-methyl(2)-butenoicacid ethyl ester requires D-tyrosine as starting material, which is anunnatural amino acid and is not readily available.

It was hence an object of the present invention to provide analternative reaction route for preparing compoundN-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoicacid ethyl ester, or salt thereof, preferably a reaction route whichavoids the above-mentioned drawbacks of the prior art process.

It was a further object of the present invention to provide analternative hydrogenation step in a process for producing NEP inhibitorsor prodrugs thereof. In particular it was an object to provide analternative process for producing compounds according to formula (1), orsalt thereof,

wherein R1 and R2 are, independently of each other, hydrogen or anitrogen protecting group, and R3 is a carboxyl group or an ester group,preferably carboxyl group or alkyl ester. Compounds of formula (1) canbe used as intermediates in the preparation of NEP inhibitors, orprodrugs thereof, in particular NEP inhibitors comprising aγ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone,preferablyN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, for example, as described in the Journal ofMedicinal Chemistry, 1995, 38, 1689.

It was a still further object to provide a process for producingcompounds according to formulae (1-a) and (1-b), or salts thereof,wherein R1, R2 and R3 are defined as above, having a high diastereomericratio. Preferably, it was an object to provide a process for obtaining adiastereomeric ratio of compounds according to formula (1-a), or saltsthereof, to compounds according to formula (1-b), or salts thereof; ofat least 80:20, more preferably of at least 90:10, most preferably aratio of (1-a) to (1-b) of at least 99:1. It was also an object toprovide a process in which the compounds according to formula (1-b), orsalts thereof, can be completely removed and compounds according toformula (1-a), or salts thereof, can be provided in pure form.

The new processes, according to the present invention, for producingcompounds according to formula (1), or salt thereof, as defined herein,are summarized in Scheme 1.

Namely, a compound of formula (8) is converted into a compound offormula (7), or salt thereof, wherein R1 is hydrogen or a nitrogenprotecting group, according to a method described in Section A. Next,the compound of formula (7), or salt thereof, as described above, isconverted into the compound of formula (1) or salt thereof, according tomethods 1 or 2, wherein

-   -   method 1 comprises    -   a) any one of the methods in Section B to convert (7) into (4),    -   b) any one of the methods in Section C to convert (4) into (2),        and    -   c) any one of the methods in Section C to convert (2) into (1);    -   method 2 comprises;    -   a) any one of the methods in Section D to convert (7) into (3),        and    -   b) conversion of the compound of formula (3) into (1), for        example, as described in European patent application 07100451.9        or WO2008/083967.

As discussed below, Sections A, B, C and D as such are also preferredembodiments of the present invention.

SECTION A: PREPARATION OF A COMPOUND OF FORMULA (7)

In one aspect, the present invention relates to a process for preparinga compound of formula (7), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, said process comprising reacting a compound offormula (8), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, with an amine offormula (13), (14) or (15), or mixtures thereof,

wherein each R6 and each R7 are, independently, an alkyl group, an arylgroup, an arylalkyl group, a cycloalkyl group or together R6 and R7 forma cycle, together with the nitrogen to which they are attached, whichcycle may be saturated or unsaturated and may optionally contain one ormore heteroatoms, such a nitrogen, oxygen or sulphur, whereby the cyclecontains 3 to 8, such as 4 to 7 ring atoms, and each R8 is,independently, an alkyl group, an aryl group or an arylalkyl group toobtain the compound of formula (7).

The reaction to obtain the enamine of formula (7) can take place neat orin any inert solvent, preferably in an aprotic solvent such ashalogenated hydrocarbons, such as methylene chloride; ethers, such asTHF, dimethoxyethane, or dioxane; or aromatic solvents such as benzene,chlorobenzene, toluene, phenylethane or xylenes or mixtures thereof.Preferably the solvent is toluene or THF. Typically, the reaction can beconducted at 0° C. to reflux, preferably 0 to 200° C., more preferably20 to 140° C., yet more preferably 40 to 100° C., most preferably 60 to90° C.

Preferred examples of the amines of formulae (13), (14) and (15) includeBredereck's reagent {tert-butoxybis(dimethylamino)methane},tert-butoxybis(diethylamino)methane, methoxybis(dimethylamino)methane,tert-pentoxy-bis(dimethylamino)methane, tris(dimethylamino)methane,tris(diethylamino)methane, and N,N-dimethylformamide dimethylacetal(DMFDMA), N,N-dimethylformamide diethylacetal, N,N-dimethylformamidediisopropylacetal, N,N-dimethylformamide di-tert-butylacetal,N,N-dimethylformamide di-tert-pentoxyacetal, or mixtures thereof.

In one embodiment the amine of formula (14) is preferably theBredereck's reagent or tert-pentoxy-bis(dimethylamino)methane. Inanother embodiment, the amine of formula (13) is preferablytris(dimethylamino)methane. In still another embodiment, the amine offormula (15) is preferably N,N-dimethylformamide di-tert-butylacetal orN,N-dimethylformamide di-tert-pentoxyacetal. The amine of formulae (13),(14) or (15), or mixtures thereof, can be used in an amount of 1.0 to 10equivalents, preferably 3 to 10 equivalents, more preferably 3 to 6equivalents, such as 3 equivalents. Optionally, an alcohol may bepresent, preferably an alkyl alcohol such as 1-butanol, 2-butanol,tert-butanol or 2-methyl-2-butanol. Typically, the alcohol can be usedin an amount of 1.0 to 10 equivalents, preferably 3 to 10 equivalents,more preferably 3 to 6 equivalents, such as 3 equivalents. In oneembodiment, the alcohol can be used with (13) to make (14) and/or (15)in situ.

These amines can be purchased from suppliers, such as Aldrich, Fluka orAcros, or can be obtained according to methods known in the art, forexample as described in Adv. Synth. Catal., 2004, 346, 1081;Encyclopedia of Reagents for Organic Synthesis, 2007, DOI:10.1002/9780470842898.rb350.pub2; Tetrahedron Lett., 1983, 25, 285;Encyclopedia of Reagents for Organic Synthesis, 2007, DOI:10.1002/047084289X.rt403; Synlett, 2006, 809; Recueil des travauxchimiques des Pays-Bas, 1969, 88, 289; J. Org. Chem., 1985, 50, 3573; J.Org. Chem., 1980, 45, 3986; Chem. Ber., 1968, 101, 1885; J. Chem. Soc.,Perkin Trans. 2, 1985, 1669; Angew. Chem., Int. Ed., 1962, 1, 331; Chem.Ber., 1968, 101, 41; Chem. Ber., 1968, 101, 51; Liebigs Ann. Chem.,1972, 762, 62; Science of Synthesis, 2005, 22, 795; J. Am. Chem. Soc.,1961, 83, 2588 or in J. Org. Chem., 1962, 27, 3664, or according tomethods in Section F of the present invention.

In one embodiment, the conversion of a compound of formula (8) into acompound of formula (7), as described above, takes place in the presenceof a salt, for example an alkali metal salt (eg a salt of lithium,sodium or potassium), an alkaline earth metal salt (eg a salt ofmagnesium or calcium) or an ammonium salt, wherein the couterion is, forexample, a halide, a carbonate, an amine, perchlorate,hexafluorophosphate or hexafluorosilicate. In particular, the salt isselected from lithium hexafluorophosphate (LiPF₆), sodiumhexafluorophosphate (NaPF₆), potassium hexafluorophosphate (KPF₆),ammonium hexafluorophosphate (NH₄ PF₆), lithium chloride (LiCl), lithiumbromide (LiBr), sodium chloride (NaCl), potassium chloride (KCl),magnesium chloride (MgCl₂), potassium perchlorate (KClO₄), sodiumhexafluorosilicate (Na₂SiF₆), lithium amide (LiNH₂) and lithiumcarbonate (Li₂CO₃). The salt may also be an ionic liquid, such as1-butyl-3-methyl imidazolium tetrafluoroborate or 1-butyl-3-methylimidazolium hexafluorophosphate. In one embodiment, the salt is lithiumhexafluorophosphate, lithium chloride, magnesium chloride, or potassiumhexafluorophosphate.

In another embodiment, the conversion of a compound of formula (8) intoa compound of formula (7), as described above, takes place in thepresence of a salt, as described above, and an amine. Typically, theamine is a secondary amine, such as a secondary amine of the formulaHNR6R7 wherein R6 and R7 are independently as defined above forcompounds of formula 13, 14 or 15. In particular, the amine isdiphenylamine, diisopropylamine, dimethylamine or imidazole. Optionally,a base may be added to the amine of formula HNR6R7 to give a species ofthe formula M-NR6R7 wherein M is an alkali metal (eg lithium sodium,potassium) or an alkaline earth metal (eg magnesium, calcium) and R6 andR7 are independently as defined above. In particular, M is an alkalimetal, such as lithium. In one embodiment, the base is LHMDS and theamine is diphenylamine.

In yet a further embodiment, the conversion of a compound of formula (8)into a compound of formula (7), as described above, takes place in thepresence of a salt, as described above, and a crown ether. Inparticular, the salt is potassium hexafluorophosphate and the crownether is 18-crown-6.

Typically, in the above embodiments, the salt may be used in a catalyticor in a stoichiometric amount with respect to the compound of formula(8). In particular, the salt may be used in an amount of, for example,0.1 to 2 equivalents, in particular 0.5 to 2 equivalents, such as 1 to 2equivalents.

In a preferred case, suitable reagents for preparing a compound offormula (7), or a salt thereof, from a compound of formula (8), or asalt thereof, involves reacting a compound of formula (7) with acompound prepared by mixing a compound of formula (18),

wherein R6 and R7 are, independently, defined as before, with analcoholate of the formula M-OR8wherein,X is defined as an anion, for example, a halide (eg chloride, bromide,iodide), an anion of a sulphonic acid (eg trifluoromethanesulfonic acid,methanesulphonic acid, 4-toluenesulphonic acid), an anion of analkylsulfate (eg methylsulfate), a tetrahalometalate, for example, atetrachlorometalate (eg tetrachloromanganate, tetrachloroaluminate),hexafluorophosphate, hexafluoroantimonate, tetrafluoroborate,perchlorate, alkoxide, for example, R8O⁻ where R8 is defined as before(eg tert-butoxide, phenoxide), carboxylate, tribromide.

M is defined as an alkali metal (eg lithium, sodium, potassium, inparticular sodium, potassium) or an alkaline earth metal (eg magnesium,calcium).

R8 is defined as before.

R8O is defined as an alkoxy group.

The reaction may be performed neat or in any inert solvent, as definedabove.

In a preferred case, an alcoholate of the formula M-OR8 is added,optionally in a solvent for example an inert solvent such astetrahydrofuran, methyltetrahydrofuran, toluene, alkanes (such asheptane, hexane), or mixtures thereof, to a compound according toformula (18), optionally in an inert solvent. M-OR8 is typically used inthe range 0.5 to 1.5 equivalents, more preferably in the range 0.8 to1.2 equivalents.

Typically the mixture is stirred, typically at 0° C. to reflux,preferably 0 to 120° C., more preferably 20 to 80° C.

The mixture is reacted with a compound according to formula (8), or asalt thereof, to provide a compound according to formula (7), or a saltthereof.

In a preferred case, the mixture can be used in an amount of 1.0 to 10equivalents, preferably 3 to 10 equivalents, more preferably 3 to 6equivalents, such as 3 equivalents. Typically, the equivalents used arerelative to the compound according to formula (18). Typically, thereaction can be conducted at 0° C. to reflux, preferably 0 to 120° C.,more preferably 20 to 80° C.

In one embodiment, the mixture of an alcoholate of the formula M-OR8 anda compound according to the formula (18), optionally in a solvent asdefined above, which may be prepared as described above, is reacted witha compound according to formula (8). The mixture can be added to (8) inan amount of 1.0 to 10 equivalents, in particular 3 to 10 equivalents,such as 3 to 6 equivalents, in particular 3 equivalents. When the amountof alcoholate M-OR8 and a compound according to the formula (18) are notequimolar amounts, the equivalents of the mixture used in relation to(8) are relative to the amount of (18). Typically, the reactioninvolving the mixture of alcoholate of the formula M-OR8 and a compoundaccording to the formula (18), optionally in a solvent as defined above,is conducted at 0° C. to reflux, in particular 0 to 120° C., such as 20to 80° C.

Compound of the formula (7) can be optionally isolated as a residue byremoval of volatile substances from the mixture. The distillate maycontain an amine of formula (13), (14) or (15), or mixtures thereof.Where a solid is present after formation of a compound of the formula(7), this may be optionally removed, for example by filtration, prior todistillation. The solid may contain a compound of formula (18).

In a further preferred case, a compound according to formula (18),optionally in the presence of an alcoholate of formula R8O-M, may betreated with a salt of formula M1X′, which partially or fully exchangesthe anionic counterion (X) of compounds according to formula (18) by ananionic counterion (X′), wherein X′ is defined as described above for Xand M1 is an alkali metal (eg lithium, sodium or potassium), an alkalineearth metal (eg magnesium or calcium) or ammonium, in order to givecompounds of the formula (18′).

Suitable reagents for this exchange include alkali metal salts (such aslithium, sodium or potassium tetrafluoroborate or hexafluorophosphate,sodium methylsulfate, sodium perchlorate), alkaline earth metal salts(such as magnesium or calcium perchlorate), ammonium salts (such asammonium tetrafluoroborate or hexafluorophosphate). Preferablyhexafluorophosphate salts or tetrafluoroborate salts are used, morepreferably ammonium hexafluorophosphate or ammonium tetrafluoroborate orsodium tetrafluoroborate is used. Most preferably hexafluorophosphatesalts are used, preferably ammonium hexafluorophosphate. Relative to theanionic counterion (X), the anionic counterion (X′) of suitable reagentsmay be used in catalytic or stoichiometric quantities.

The mixture obtained after such an exchange may be used as-is, such thatthe mixture contains both (18) and (18′), and optionally R8O-M.Alternatively, the anion of formula (X) may be removed from the mixture,for example by filtration, such that the mixture subsequently contains(18′), and optionally R8O-M.

Furthermore, compounds of formula (18) or (18′) or mixtures thereof, aresuitable reagents for the present invention. Compounds according to theformula (18′) are, independently, defined according to compoundsaccording to the formula (18).

As such, in a preferred case, a compound of formula (8) is convertedinto a compound according to formula (7) by reaction with a compound offormula (18) and an alcoholate of formula R8O-M, optionally in thepresence of a compound of formula (18′).

Furthermore, in a preferred case, a compound of formula (8) is convertedinto a compound according to formula (7) by reaction with a compound offormula (18) and an alcoholate of formula R8O-M, optionally in thepresence of a compound of formula (18′) and an amine of formula (13),(14) or (15), or mixtures thereof.

Optionally, a compound of formula (8) can be converted into a compoundaccording to formula (7) by reaction with a compound of formula (18) andan alcoholate of formula R8O-M optionally in the presence of a compoundof formula (18′) and an amine of formula (13), (14) or (15), or mixturesthereof, in the presence of an amine, typically of the formula HNR6R7,where R6 and R7 are independently as defined above. In particular, theamine is diphenylamine, diisopropylamine, dimethylamine or imidazole.Optionally, a base may be added to the amine of formula HNR6R7 to give aspecies of formula M-NR6R7 where M is an alkali metal (eg lithiumsodium, potassium) or an alkaline earth metal (eg magnesium, calcium)and R6 and R7 are independently as defined above. In particular, M is analkali metal, such as lithium. In one embodiment, the base is LHMDS andthe amine is diphenylamine.

Compounds of the formula (18) or (18′) can be purchased from supplierssuch as Aldrich and Fluka, or can be obtained according to methods knownin the art, for example, as described in J. Chem. Soc., Perkin Trans. 1,2001, 1586; J. Chem. Soc., Perkin Trans. 1, 1987, 845; Synthesis, 1977,273; Science of Synthesis, 2005, 22, 221; Synthesis Communications,1983, 785; Recueil des travaux chimiques des Pays-Bas, 1969, 88, 289;Chem. Res. Chinese U., 2005, 21, 177; Chem. Ber., 1993, 126, 1859;Synthetic Communications, 1998, 28, 1223; J. Org. Chem., 1965, 2464; J.Org. Chem., 1970, 35, 1542; Liebigs Ann. Chem., 1972, 762, 62; J. Am.Chem. Soc., 1961, 83, 2588; J. Org. Chem., 1962, 27, 3664 or J. Chem.Soc., 1949, 3319, or according to methods in Section F of the presentinvention.

Compounds of the formula R8O-M can be purchased from suppliers such asAldrich, BASF, Chemetall GmbH, or can be obtained according to methodsknown to persons skilled in the art.

The following preferences apply:

For compounds of formula (18) or (18′), R6 and R7 are, independently, analkyl group, an aryl group, an arylalkyl group, a cycloalkyl group ortogether R6 and R7 form a cycle, together with the nitrogen to whichthey are attached, which cycle may be saturated or unsaturated and mayoptionally contain one or more heteroatoms, such a nitrogen, oxygen orsulphur, whereby the cycle contains 3 to 8, such as 4 to 7 ring atoms.Most preferably, R6 is alkyl. Still more preferably R6 is methyl orethyl and R7 is methyl or ethyl. X is preferably chloride,methylsulfate, tetrafluoroborate or hexafluorophosphate. Mostpreferably, X is chloride or hexafluorophosphate. In a preferred case,compounds of formula (18) or (18′) are preferablyN,N,N,N-tetramethylformamidinium or N,N,N,N-tetraethylformamidiniumchloride, N,N,N,N-tetramethylformamidinium orN,N,N,N-tetraethylformamidinium hexafluorophosphate

For compounds of the formula R8O-M, R8 is preferably alkyl, mostpreferably tert-butyl or amylate. M is preferably an alkali metal, mostpreferably sodium or potassium. Further preferred is when R8O-M issodium tert-butoxide (NaOCMe₃) or potassium tert-butoxide (KOCMe₃) orsodium amylate (NaOCMe₂Et) or potassium amylate (KOCMe₂Et). Mostpreferred is when R8O-M is potassium tert-butoxide or sodium amylate.

SECTION B: PREPARATION OF A COMPOUND OF FORMULA (4)

The processes, according to the present invention, to convert of acompound of formula (7), as defined herein, into a compound of formula(4), as defined herein, are outlined in Scheme 2.

The present invention relates thus to the conversion of a compound offormula (7), as described herein, into a compound of formula (4), asdescribed herein, according to any one of methods 1 to 9, wherein

method 1 comprises

-   -   a) any one of methods in Section B.1 to convert (7) into (6),        and    -   b) any one of methods in Section B.2.1 to convert (6) into (4);        method 2 comprises    -   a) any one of methods in Section B.1 to convert (7) into (6),    -   b) any one of methods in Section B.2.2 to convert (6) into (5),        and    -   c) any one of methods in Section B.2.3 to convert (5) into (4);        method 3 comprises any one of methods in Section B.3.1 to        convert (7) into (4);        method 4 comprises    -   a) any one of methods in Section B.3.2 to convert (7) into (6),        and    -   b) any one of methods in Section B.2.1 to convert (6) into (4);        method 5 comprises    -   a) any one of methods in Section B.3.2 to convert (7) into (6),    -   b) any one of methods in Sections B.2.2 to convert (6) into (5),        and    -   c) any one of methods in Section B.2.3 to convert (5) into (4);        method 6 comprises    -   a) any one of methods in Section B.3.3 to convert (7) into (9),    -   b) any one of methods in Section B.4 to convert (9) into (10),        and    -   c) any one of methods in Section B.4 to convert (10) into (4);        method 7 comprises    -   a) any one of methods in Section B.3.4 to convert (7) into (5),        and    -   b) any one of methods in Section B.2.3 to convert (5) into (4);        method 8 comprises    -   a) any one of methods in Section B.5.1 to convert (7) into (16),    -   b) any one of methods in Section B.5.2 to convert (16) into (6),    -   c) any one of methods in Section B.2.2 to convert (6) into (5),        and    -   d) any one of methods in Section B.2.3 to convert (5) into (4);        method 9 comprises    -   a) any one of methods in Section B.5.1 to convert (7) into (16),    -   b) any one of methods in Section B.5.2 to convert (16) into (6),        and    -   c) any one of methods in Section B.2.1 to convert (6) into (4);        preferably the conversion of a compound of formula (7), as        described herein, into a compound of formula (4), as described        herein, is according to methods 1, 4 or 6; in particular methods        1 or 4.

As discussed below, Sections B.1, B.2.1, B.2.2, B.2.3, B.3.1, B.3.2,B.3.3, B.3.4, B.4, B.5.1 and B.5.2 as such are also preferredembodiments of the present invention.

Section B.1:

In another aspect, the present invention relates to a process forpreparing a compound of formula (6) or a tautomer thereof.

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,comprising treating a compound of formula (7), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and R6 and R7 are,independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, with an acid to obtain the compound of formula (6),preferably of the formula (6-a). In a preferred embodiment, the startingcompound of formula (7), or salt thereof, is according to formula (7-a),or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and R6 and R7 are,independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, more preferably the starting compound of formula (7),is according to formulae (7b) or (7c), or salts thereof, most preferablyaccording to formula (7-b), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and R6 and R7 are,independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms.

The compound of formula (6), or salt thereof, preferably of formula(6-a), or a tautomer thereof, which is obtained according to the aboveprocess can be isolated or used as a solution in a subsequenttransformation, for example conversion into the compound of formula (4),or salt thereof, as defined herein.

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (6-a), or a tautomer thereof

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,comprising treating a compound of formula (7-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and R6 and R7 are,independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, with an acid to obtain the compound of formula (6-a).In a preferred embodiment, the starting compound of formula (7-a), orsalt thereof, is according to formula (7-b), as defined above.

Preferred examples of acid are aqueous mineral acids, such ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.Most preferred is aqueous sulfuric acid. Preferably, the amount of acidemployed is such that the pH of the reaction mixture is of from 1 to 7,more preferably pH of from 2 to 5, most preferably pH of from 2 to 3. Asolvent can be used, preferably one that is miscible or partly misciblein water, for example acetonitrile. Optionally, a phase transfercatalyst, such as tetra-n-butylammonium halide, for exampletetra-n-butylammonium bromide, can be added. Typically the reaction canbe conducted at −20 to 30° C., preferably −20 to 20° C., more preferably−10 to 10° C., most preferably 0 to 10° C.

Section B.2: Section B.2.1:

In another aspect, the present invention relates to a process forpreparing a compound of formula (4)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,comprising treating a compound of formula (6), or salt or a tautomerthereof,

wherein R1 is hydrogen or a nitrogen protecting group,with a reducing agent, preferably in the form of an aldehyde, to obtainthe compound of formula (4). In a preferred embodiment, the startingcompound of formula (6), or salt thereof, is according to formula (6-a),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group.

In a preferred embodiment, a compound of formula (6-a), or salt, or atautomer thereof,

wherein R1 is hydrogen or a nitrogen protecting group,is treated with a reducing agent, preferably in the form of an aldehyde,to obtain a compound of formula (4-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group.

The reducing agent is typically an aldehyde, more preferably anon-enolisable aldehyde, even more preferably an arylaldehyde, such asbenzaldehyde, or a trihaloacetaldehyde, such as chloral, yet morepreferably formaldehyde, such as monomeric formaldehyde (obtained by,e.g. ‘cracking’ paraformaldehyde), 1,3,5-trioxane, paraformaldehyde oran aqueous solution of formaldehyde (for example 37% in water).

Preferably, the reduction of the compound of formula (6), or saltthereof, preferably of the formula (6-a), or salt thereof, is carriedout at pH of from 7, more preferably pH of from 7 to 14, most preferablypH of from 10 to 11. A base is used to maintain pH of from 7. Suitablebases are weak bases or strong bases or mixtures of thereof. Preferably,the base is an alkali metal carbonate, such as potassium carbonate, oras metal alkali hydroxide, such as sodium hydroxide. Most preferably thebase is potassium carbonate. In a preferred embodiment, the reduction isperformed as a biphasic mixture of water and an organic solvent,preferably in the presence of a phase transfer catalyst such astetrabutylammonium hydroxide.

Section B.2.2:

In a particular embodiment, treatment of the compound of formula (6), orsalt thereof, as defined above, with a reducing agent, preferably withhydrogen and a transition metal catalyst (eg a palladium catalyst) forexample as described in Section B.3.3, leads to a compound of formula(5), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,or leads to a mixture of the compounds of formulae (4) and (5).

In another particular embodiment, treatment of the compound of formula(6-a), or salt thereof, as defined above, with a reducing agent,preferably with hydrogen and a transition metal catalyst (eg a palladiumcatalyst) for example as described in Section B.3.3, leads to a compoundof formula (5-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, preferably offormula (5-b),

or leads to a mixture of the compounds of formulae (4-a) and (5-a),preferably a mixture of the compounds of formulae (4-a) and (5-b).

Section B.2.3: Section B.2.3.1:

In a further aspect, the present invention relates to a process forpreparing a compound of formula (4)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,said process comprisinga) treating a compound of formula (5), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,with an OH-activating agent to obtain a compound of formula (11)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R4 is an OH-activating group; andb) reacting the compound of formula (11), or salt thereof, with a baseto obtain the compound of formula (4).

Steps a) and b) as such are also an embodiment of the present invention.

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (4-a)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,said process comprisinga) treating a compound of formula (5-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,with an OH-activating agent to obtain a compound of formula (11-a)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R4 is an OH-activating group; andb) reacting the compound of formula (11-a), or salt thereof, with a baseto obtain the compound of formula (4-a).

Steps a) and b) as such are also a preferred embodiment of the presentinvention.

Section B.2.3.2:

In a preferred embodiment, the conversion of the OH-group of thecompound of formula (5), or salt thereof, preferably of formula (5-a),into an OH-activated group occurs in the presence of the base. Accordingto this preferred embodiment, the activation of the OH-group and thesubsequent elimination of the OH-activated group occurs in situ to givethe compound of formula (4), or salt thereof, preferably of formula(5-a); i.e. without isolation of the OH-activated compound of theformula (11), or salt thereof, preferably of formula (11-a).

In a more preferred embodiment, the present invention relates to aprocess for preparing a compound of formula (4-a)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,comprising treating a compound of formula (5-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,with an OH-activating agent in the presence of a base to obtain thecompound of formula (4-a).

In the above described methods (Sections B.2.3.1 and B.2.3.2), anOH-activating agent is any reagent which can convert a hydroxyl groupinto a leaving group. Examples of suitable OH-activating agents aresulphonating agents, such as methanesulfonyl- or toluenesulfonylhalides, for example methanesulfonylchloride or toluenesulfonylchloride.Preferred base is, for example, an amine, such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,6-lutidine,diisopropylethylamine, a metal hydride, such as sodium or potassiumhydride, or bases such as lithium, sodium or potassiumbis(trimethylsilyl)amide and butyllithium.

The conversion of the compound of the formula (5), preferably of theformula (5-a), or salts thereof, into the compound of formula (4),preferably of the formula (4-a), or salts thereof, can also beperformed, as described in methods above, on a mixture of compounds (4)and (5), preferably a mixture of compounds (4-a) and (5-a), or saltsthereof, as shown in Scheme 3.

Section B.2.3.3:

In a further aspect, the present invention relates to a process forpreparing a compound of formula (4)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,said process comprisinga) treating a compound of formula (5), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,with an OH-activating agent to obtain a compound of formula (11)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R4 is an OH-activating group; andb) converting the compound of formula (11), or salt thereof, into acompound of formula (12)

or a salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R5 is a leaving group; andc) reacting the compound of formula (12), or salt thereof, with a baseto obtain the compound of formula (4)

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (4-a)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,said process comprisinga) treating a compound of formula (5-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,with an OH-activating agent to obtain a compound of formula (11-a)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R4 is an OH-activating group; andb) converting the compound of formula (11-a), or salt thereof, into acompound of formula (12-a).

or a salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R5 is a leaving group; andc) reacting the compound of formula (12-a), or salt thereof, with a baseto obtain the compound of formula (4-a).

The conversion of the −OR4 group of the compound of formulae (11) or(11-a) into a leaving group is a well-known reaction to the personskilled in the art, for example as described in Richard C. Larock,“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations”, Second Edition, Wiley-VCH Verlag GmbH, 2000, inparticular as described in the relevant chapters thereof; for example itmay be effected by the use of a metal halide, such as an alkali metalhalide or an alkaline earth metal halide. In one embodiment the metalhalide is, for example, sodium iodide.

Preferred leaving groups are halo, such as bromo or iodo.

Preferred examples of a base in step c) are amine bases, for example,triethylamine.

In one embodiment, the conversion of a compound according to formula(12), preferably of formula (12-a), into a compound according to formula(4), preferably of formula (4-a), is performed in the presence of areagent which can change the identity of R1. In one embodiment, acompound according to the formula (12-a) wherein R1=H and R5=I istreated with a base (eg triethylamine) and the reagent di-tert-butyldicarbonate to give a compound according to the formula (4-a) whereinR1=Boc.

Section B.2.3.4:

In a further aspect, the present invention relates to a process forpreparing a compound of formula (4)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,said process comprisinga) converting a compound of formula (5), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,into a compound of formula (12)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R5 is a leaving group; andb) reacting the compound of formula (12), or salt thereof, with a baseto obtain the compound of formula (4).

Steps a) as such is also an embodiment of the present invention.

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (4-a)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,said process comprisinga) converting a compound of formula (5-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,into a compound of formula (12-a)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R5 is a leaving group; andb) reacting the compound of formula (12-a), or salt thereof, with a baseto obtain the compound of formula (4-a).

The conversion of the hydroxyl group of the compound of formulae (5) or(5-a) into a leaving group is a well-known reaction to the personskilled in the art, for example as described in Richard C. Larock,“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations”, Second Edition, Wiley-VCH Verlag GmbH, 2000, inparticular as described in the relevant chapters thereof; for example itmay be effected by the use of PPh₃ and I₂.

Section B.3: Section B.3.1:

In another aspect, the present invention relates to a process forpreparing a compound of formula (4)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,comprising treating a compound of formula (7),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand, R6 and R7 are, independently, an alkyl group, an aryl group, anarylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle,together with the nitrogen to which they are attached, which cycle maybe saturated or unsaturated and may optionally contain one or moreheteroatoms, such a nitrogen, oxygen or sulphur, whereby the cyclecontains 3 to 8, such as 4 to 7 ring atoms,with a reducing agent to obtain the compound of formula (4), preferablyof the formula (4-a). In a preferred embodiment, the starting compoundof formula (7), or salt thereof, is according to formula (7-a), or saltthereof, as defined above; more preferably the starting compound isaccording to formulae (7-b) or (7-c), or salts thereof, as definedabove, most preferably the starting compound is according to formula(7-b), or salts thereof, as defined above.

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (4-a)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group,comprising treating a compound of formula (7-a),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand, R6 and R7 are, independently, an alkyl group, an aryl group, anarylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle,together with the nitrogen to which they are attached, which cycle maybe saturated or unsaturated and may optionally contain one or moreheteroatoms, such a nitrogen, oxygen or sulphur, whereby the cyclecontains 3 to 8, such as 4 to 7 ring atoms,with a reducing agent to obtain the compound of formula (4-a). In apreferred embodiment, the starting compound of formula (7), or saltthereof, is according to formulae (7-b) or (7-c), or salts thereof, asdefined above, preferably of formula (7-b).

Preferred reducing agents are hydrides, such as metal alkaliborohydrides, for example sodium borohydride, lithium borohydride,potassium borohydride, calcium borohydride, sodiumtriacetoxyborohydride, tetramethylammonium borohydride ortriacetoxyborohydride, and alkali metal hydrides, for example, lithiumaluminium hydride, L-Selectride®, K-Selectride®, N-Selectride® ordiisobutylaluminium hydride. Preferred reducing agents are sodiumtriacetoxyborohydride and diisobutylaluminium hydride; more preferablydiisobutylaluminium hydride; most preferably diisobutylaluminium hydridein THF. Preferably, the reaction takes place in an ethereal solvent,such as THF, dimethoxyethane, or dioxane; preferably the solvent is THF.Typically the reaction can be conducted at −78 to 30° C., preferably −20to 25° C., more preferably 15 to 25° C.

Section B.3.2:

In yet another embodiment, the treatment of the compound of formula (7),or salt thereof, as defined above, with a reducing agent, preferablywith hydrogen and a transition metal catalyst (eg a palladium catalyst)for example as described in Section B.3.3, can lead to a compound offormula (6), or salt thereof, as defined above, or can lead to a mixtureof the compounds of formulae (4) and (6).

In still another embodiment, treatment of the compound of formula (7-a),or salt thereof, as defined above, with a reducing agent leads to acompound of formula (6-a), or salt thereof, as defined above, or leadsto a mixture of the compounds of formulae (4-a) and (6-a).

Section B.3.3:

In a further embodiment, the treatment of the compound of formula (7),or salt thereof, as defined above, with a reducing agent, preferablywith hydrogen and a transition metal catalyst, can lead to a compound offormula (9), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, or can lead to a mixture of the compounds of formulae(4) and (9).

In yet a further embodiment, the treatment of the compound of formula(7-a), or salt thereof, as defined above, with a reducing agent,preferably with hydrogen and a transition metal catalyst, leads to acompound of formula (9-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms. In one embodiment, the compound of formula (9-a), orsalt thereof, is according to formula (9-b),

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms. In another embodiment, the compound of formula (9-a),or salt thereof, is according to formula (9-c),

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms.

In one embodiment, the reduction of the compound of formula (7), or saltthereof, preferably of formula (7-a), takes place with hydrogen in thepresence of a transition metal catalyst, wherein the transition metal isselected from group 9 or 10 of the periodic table. Therefore, thetransition metal catalyst comprises, for example, Cobalt (Co), Rhodium(Rh), Iridium (Ir), Nickel (Ni), Palladium (Pd) and/or Platinum (Pt).The reduction may occur under hetereo- or homogeneous hydrogenationconditions, preferably under heterogeneous hydrogenation conditions. Inparticular, the transition metal is selected from Pt, Pd, or Ir; whereinthe transition metal may optionally be poisoned by, for example, sulfuror lead. Examples of poisoned transition metals are Pd(S), Pd(Pb) orPt(S). In particular, the transition metal catalyst comprises atransition metal on a solid support. The loading of the transition metalon the solid support is, for example, of from 1% to 10% w/w. Solidsupports are, for example, carbon, metal oxides (e.g. aluminium oxide,zirconium oxide, titanium oxide or silicon dioxide/aluminium oxide),sulfates (e.g. barium sulfate) or carbonates (e.g. calcium carbonate andbarium carbonate). In one embodiment, the transition metal catalyst maycontain water, for example, of from 0 mass % to 61 mass % content ofwater.

In one embodiment, the hydrogenation takes place in the presence of abase, such as amine bases (e.g. triethylamine) or alkali metal bases(e.g. cesium carbonate or potassium carbonate).

In particular, the transition metal is palladium and the solid supportis, for example, carbon, metal oxides (e.g. aluminium oxide, zirconiumoxide, titanium oxide or silicon dioxide/aluminium oxide), carbonates(e.g. calcium carbonate and barium carbonate) or sulfates (e.g. bariumsulfate).

In one embodiment, the transition metal catalyst is a Pd catalystselected from the group consisting of palladium on carbon, such as 1%Pd/C (e.g. 1% Pd/C type 39), 3% Pd/C (e.g. 3% Pd/C type 39), 5% Pd/C(e.g. 5% Pd/C A401102-5, 5% Pd/C A401102, 5% Pd/C A109047, 5% Pd/CA405028, 5% Pd/C A405032, 5% Pd/C A405038, 5% Pd/C A503023, 5% Pd/CA503032, 5% Pd/C A503038, 5% Pd/C A102023, 5% Pd/C A102038, 5% Pd/C type374, 5% Pd/C type 398, 5% Pd/C type 37, 5% Pd/C type 87L, 5% Pd/C type487, 5% Pd/C type 39, 5% Pd/C type 394, 5% Pd/C type 487 (powder), 5%Pd/C type 472 (powder), 5% Pd/C type 87L (powder), 5% Pd/C Type 5R394,5% Pd/C Type 5R338 or 5% Pd(S)/C [e.g. 5% Pd(S)/C A103038]), or 10% Pd/C(e.g. 10% Pd/C type 374, 10% Pd/C type 394, 10% Pd/C type 87L or 10%Pd/C type 37); of palladium on aluminium oxide, such as 5% Pd/Al₂O₃(e.g. 5% Pd/Al₂O₃ A302084-5 or 5% Pd/Al₂O₃ A302011); of palladium oncalcium carbonate, such as 5% Pd/CaCO₃ (e.g. 5% Pd/CaCO₃ A303060 or 5%Pd/CaCO₃ type 405) or 5% Pd(Pb)/CaCO₃ (e.g. 5% Pd(Pb)/CaCO₃ A 305060);of palladium on titanium oxide, such as 5% Pd/TiO₂ (e.g. 5% Pd/TiO₂C6944); of palladium on barium sulfate, such as 5% Pd/BaSO₄ (e.g. 5%Pd/BaSO₄ A 308053); of palladium on zirconium oxide, such as 5% Pd/ZrO₂(e.g 5% Pd/ZrO₂ C7140); and of palladium on silicon dioxide/aluminiumoxide, such as 5% Pd/SiO₂/Al₂O₃ (e.g. 5% Pd/SiO₂/Al₂O₃ C7078 or 5%Pd/SiO₂/Al₂O₃ C7079); which are commercially available, for example fromJohnson Matthey.

In another embodiment, the transition metal catalyst is a Pt catalystsuch as platinum on carbon, for example 5% Pt/C (e.g. 5% Pt/C B103032,5% Pt/C B103018, 5% Pt/C B103014, 5% Pt/C B104032, 5% Pt/C B 501032, 5%Pt/C B109032 or 5% Pt/C B501018) or 5% Pt(S)/C (e.g 5% Pt(S)/C B106032);which are commercially available, for example from Johnson Matthey.

In another embodiment, the transition metal catalyst is an Ir catalystsuch as iridium on carbon, for example 5% Ir/C (e.g. 5% Ir/C C-7750) oron calcium carbonate, for example 5% Ir/CaCO₃ (e.g. 5% Ir/CaCO₃ type30); which are commercially available, for example from Johnson Matthey.

The amount of transition metal catalyst to substrate, typically employedin the process, may be in the range of from 1 to 75 wt %, preferably offrom 10 to 50 wt %, more preferably of from 20 to 50 wt %.

Solvents generally known in the art can be used. Preferred solvents are,for example, alcohol solvents (e.g. methanol, ethanol or isopropanol),ether solvents (e.g. tetrahydrofuran, methyltetrahydrofuran ortetrahydrofuran/water), aromatic solvents (e.g. toluene) or estersolvents (e.g. ethyl acetate or isopropyl acetate). In one embodimentthe solvent is ethanol or tetrahydrofuran. The amount of solventemployed may be such that the concentration of substrate is in a therange of from 0.01 to 1 M, such as 0.05 M, in particular of from 0.1 to0.5 M or of from 0.1 to 0.3 M.

The hydrogenation usually is carried out at a temperature of from 20° C.to 100° C., in particular of from 25° C. to 75° C., such as; of from 30°C. to 75° C., of from 45° C. to 75° C., of from 25° C. to 65° C. or offrom 25° C. to 55° C. The applied hydrogen pressure usually ranges offrom 1 bar to 40 bar, such as of from 3 bar to 30 bar, in particular; offrom 5 bar to 30 bar, of from 3 bar to 20 bar or of from 3 bar to 10bar.

In the above hydrogenation reaction the stereochemistry might be ofimportance. Thus, it is a further object to provide a process forproducing compounds according to formulae (9-b) and (9-c), or saltsthereof, as defined above, wherein the molar ratio of compoundsaccording to formula (9-b), or salts thereof, to compounds according toformula (9-c), or salts thereof, is at least 50 to 50, in particular atleast 60 to 40, such as at least 71 to 29, in particular at least 82 to18. In particular, this objective can be achieved by using a transitionmetal catalyst such as a Pd or Pt catalyst; for example: palladium oncarbon, such as 5% Pd/C (e.g. 5% Pd/C A401102-5, 5% Pd/C A401102, 5%Pd/C A109047, 5% Pd/C A503038, 5% Pd/C A405028, 5% Pd/C A405038, 5% Pd/CA503023, 5% Pd/C A102023, 5% Pd/C type 37, 5% Pd/C type 39, 5% Pd/C type394, 5% Pd/C type 87L), 5% Pd(S)/C [e.g. 5% Pd(S)/C A103038], 5% Pd/CType 5R394 or 5% Pd/C Type 5R338), 10% Pd/C (e.g. 10% Pd/C type 394 or10% Pd/C type 37), 1% Pd/C (e.g. 1% Pd/C type 39) or 3% Pd/C (e.g. 3%Pd/C type 39); palladium on barium sulfate, such as 5% Pd/BaSO₄ (e.g. 5%Pd/BaSO₄ A 308053); palladium on aluminium oxide, such as 5% Pd/Al₂O₃(e.g. 5% Pd/Al₂O₃ A302084-5); palladium on calcium carbonate, such as 5%Pd/CaCO₃ (e.g 5% Pd/CaCO₃ A303060); palladium on zirconium oxide, suchas 5% Pd/ZrO₂ (e.g 5% Pd/ZrO₂ C7140); or platinum on carbon, for example5% Pt/C (e.g. 5% Pt/C B103032, 5% Pt/C B103018, 5% Pt/C B103014, 5% Pt/CB104032, 5% Pt/C B 501032, 5% Pt/C B109032 or 5% Pt/C B501018) or 5%Pt(S)/C (e.g 5% Pt(S)/C B106032); which are commercially available, forexample from Johnson Matthey.

Thus it is a further object to provide a process for producing compoundsaccording to formulae (9-b) and (9-c), or salts thereof, as definedabove, wherein the molar ratio of compounds according to formula (9-c),or salts thereof, to compounds according to formula (9-b), or saltsthereof, is at least 50 to 50, in particular at least 67 to 33. Inparticular, this objective can be achieved by using a transition metalcatalyst such as a Pd or Pt catalyst; for example: palladium on carbon,such as 5% Pd/C (e.g. 5% Pd/C A401102-5, 5% Pd/C A401102, 5% Pd/CA109047, 5% Pd/C A405028, 5% Pd/C A405032, 5% Pd/C A405038, 5% Pd/CA503023, 5% Pd/C A503032, 5% Pd/C A102023, 5% Pd/C A102038, 5% Pd/C type374, 5% Pd/C type 398, 5% Pd/C type 87L or 5% Pd/C type 487), 10% Pd/C(e.g. 10% Pd/C type 87L) or 5% Pd(S)/C [e.g. 5% Pd(S)/C A103038];palladium on aluminium oxide, such as 5% Pd/Al₂O₃ (e.g. 5% Pd/Al₂O₃A302084-5 or 5% Pd/Al₂O₃ A302011); palladium on calcium carbonate, suchas 5% Pd/CaCO₃ (e.g 5% Pd/CaCO₃ type 405) or 5% Pd(Pb)/CaCO₃ (e.g. 5%Pd(Pb)/CaCO₃ A 305060); palladium on titanium oxide, such as 5% Pd/TiO₂(e.g. 5% Pd/TiO₂ C6944); palladium on silicon dioxide/aluminium oxide,such as 5% Pd/SiO₂/Al₂O₃ (e.g. 5% Pd/SiO₂/Al₂O₃ C7078 or 5%Pd/SiO₂/Al₂O₃ C7079); or platinum on carbon, for example 5% Pt/C (e.g.5% Pt/C B501018); which are commercially available, for example fromJohnson Matthey.

Section B.3.4:

In one embodiment, the treatment of the compound of formula (7), or saltthereof, as defined above, with a reducing agent, preferably with ahydride reducing agent for example as described in Section B.3.1 or asdescribed in J. Chem. Soc., Perkin Trans 1, 1996, (11), 1131, can leadto a compound of formula (5), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,or can lead to a mixture of the compounds of formulae (4) and (5).

In another embodiment, treatment of the compound of formula (7-a), orsalt thereof, as defined above, with a reducing agent leads to acompound of formula (5-a), or salt thereof, as defined above, preferablyof formula (5-b), or salt thereof, or leads to a mixture of thecompounds of formulae (4-a) and (5-a), preferably a mixture of thecompounds of formulae (4-a) and (5-b).

Section B.3.5:

In another embodiment, the treatment of the compound of formula (7), orsalt thereof, as defined above, with a reducing agent, for example, asdefined in Section B.3.1 to B.3.4, can lead to a mixture of compounds offormulae (5) and (6), or salts thereof, a mixture of compounds offormulae (5) and (9), or salts thereof, a mixture of compounds offormulae (6) and (9), or salts thereof, or a mixture of compounds offormulae (5), (6) and (9), or salts thereof; wherein each mixture mayfurther comprise the compound of formula (4), or salt thereof, asdefined above. In a preferred embodiment, the treatment of the compoundof formula (7-a), or salt thereof, as defined above, with a reducingagent can lead to a mixture of compounds of formulae (5-a) and (6-a), orsalts thereof, a mixture of compounds of formulae (5-a) and (9-a), orsalts thereof, a mixture of compounds of formulae (6-a) and (9-a), orsalts thereof, or a mixture of compounds of formulae (5-a), (6-a) and(9-a), or salts thereof; wherein each mixture may further comprise thecompound of formula (4-a), or salt thereof, as defined above.

Section B.4:

In another aspect, the present invention relates to a process forpreparing a compound of formula (4), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,said process comprising reacting a compound of formula (9), or saltthereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms,with a quatemisation agent and a base to obtain the compound of formula(4).

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (4-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,said process comprising reacting a compound of formula (9-a), or saltthereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms,with a quatemisation agent and a base to obtain the compound of formula(4).

In another aspect, the present invention relates to a process forpreparing a compound of formula (4), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,said process comprisinga) reacting a compound of formula (9), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms,with a quaternisation agent to obtain a compound of formula (10), orsalt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, R6 and R7 are,independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, Z⁻ is a halide (eg iodide, bromide, chloride), analkyl sulphate (eg methyl sulphate) or a sulfonyl ester (eg triflate)and R10 is hydrogen, alkyl or aryl; andb) reacting the compound of formula (10), or salt thereof, with a baseto obtain the compound of formula (4).

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (4-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,said process comprisinga) reacting a compound of formula (9-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms,with a quatemisation agent to obtain a compound of formula (10-a), orsalt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, R6 and R7 are,independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, Z⁻ is a halide (eg iodide, bromide, chloride), analkyl sulphate (eg methyl sulphate) or a sulfonyl ester (eg triflate)and R10 is hydrogen, alkyl or aryl; andb) reacting the compound of formula (10-a), or salt thereof, with a baseto obtain the compound of formula (4-a).

Steps a) and b) as such are also preferred embodiments of the presentinvention.

The term quaternisation agent relates to any agent which is able toconvert a tertiary amine into a quaternary amine, for example, an alkylhalide (such as methyl iodide, methyl bromide, methyl chloride, ethylchloride, ethyl bromide or ethyl iodide), a dialkylsulfate (such asdimethylsulfate), a sulfonate (such as 4-methylsulfonyltoluene andmethyl triflate) or a compound of the formula (R10)₃O⁺Z⁻ wherein R10 isalkyl (such as methyl or ethyl), and Z⁻ is tetrafluoroborate orhexafluorophosphate. More preferably, the alkylating reagent is methyliodide or dimethylsulfate.

Preferred bases in step b) are, for example, amines such astriethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alsopreferred is an ionic base, such a metal alkali carbonate (for examplesodium carbonate, potassium carbonate and cesium carbonate), a metalalkali hydride (for example NaH), a metal alkali hydrogen carbonate (forexample NaHCO₃). More preferably the base is NaHCO₃.

The reaction to convert the compound of formula (9) to a compound offormula (4) is preferably ‘step-wise’ in the sense that (9) isquaternised and then treated with a base.

Section B.5: Section B.5.1

In another aspect, the present invention relates to a process forpreparing a compound of formula (16)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, Y is oxygen andeach R9, is, independently, alkyl, aryl, arylalkyl (eg benzyl) or acetylor both R9 form together a 4 to 7, preferably a 5 to 6 membered acetalring,comprising treating a compound of formula (7),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand, R6 and R7 are, independently, an alkyl group, an aryl group, anarylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle,together with the nitrogen to which they are attached, which cycle maybe saturated or unsaturated and may optionally contain one or moreheteroatoms, such a nitrogen, oxygen or sulphur, whereby the cyclecontains 3 to 8, such as 4 to 7 ring atoms,with an acetal forming agent to obtain the compound of formula (16).

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (16-a),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,Y is oxygen and each R9, is, independently, alkyl, aryl, arylalkyl (egbenzyl) or acetyl or both R9 form together a 4 to 7, preferably a 5 to 6membered acetal ring,said process comprising treating a compound of formula (7-a),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand, R6 and R7 are, independently, an alkyl group, an aryl group, anarylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle,together with the nitrogen to which they are attached, which cycle maybe saturated or unsaturated and may optionally contain one or moreheteroatoms, such a nitrogen, oxygen or sulphur, whereby the cyclecontains 3 to 8, such as 4 to 7 ring atoms,with an acetal forming agent to obtain the compound of formula (16-a).In a preferred embodiment, the starting compound of formula (7-a), orsalt thereof, is according to formulae (7b) or (7c), or salts thereof,as defined above, preferably of formula (7-b).

Preferred “acetal forming” agents are alcohols (eg methanol, ethanol,isopropanol), a diol (eg ethylene glycol, 1,3-propanediol) or a trialkylorthoformate (eg dimethyl orthoformate). Usually the reaction isperformed in the presence of an acid, for example a Brønsted acid (suchas hydrochloric acid, sulphuric acid) or a sulfonic acid (such as4-toluenesulfonic acid). Resin-bound acids such as Amberlyst-15® arealso suitable acids. Conditions whereby an acid is generated in situ (egacetyl chloride) are also appropriate. Preferably, the acid is used incatalytic quantities. Preferably a mineral acid is used, such ashydrochloric acid, preferably in the presence of an alcohol, preferablymethanol or ethanol are used. Further examples of preferred “acetalforming” reagents are described, e.g. in relevant chapters of standardreference works such as P. G. M. Wuts and T. W. Greene, “Greene'sProtective Groups in Organic Synthesis', Fourth Edition, Wiley, NewJersey, 2007.

In another aspect, the present invention relates to a process forpreparing a compound of formula (16)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, Y is sulfur andeach R9, is, independently, alkyl, aryl, arylalkyl (eg benzyl) or acetylor both R9 form together a 4 to 7, preferably a 5 to 6 memberedthioacetal ring,comprising treating a compound of formula (7),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand, R6 and R7 are, independently, an alkyl group, an aryl group, anarylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle,together with the nitrogen to which they are attached, which cycle maybe saturated or unsaturated and may optionally contain one or moreheteroatoms, such a nitrogen, oxygen or sulphur, whereby the cyclecontains 3 to 8, such as 4 to 7 ring atoms,with a thioacetal forming agent to obtain the compound of formula (16).

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (16-a),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,Y is sulfur and each R9, is, independently, alkyl, aryl, arylalkyl (egbenzyl) or acetyl or both R9 form together a 4 to 7, preferably a 5 to 6membered thioacetal ring,said process comprising treating a compound of formula (7-a),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand, R6 and R7 are, independently, an alkyl group, an aryl group, anarylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle,together with the nitrogen to which they are attached, which cycle maybe saturated or unsaturated and may optionally contain one or moreheteroatoms, such a nitrogen, oxygen or sulphur, whereby the cyclecontains 3 to 8, such as 4 to 7 ring atoms,with a thioacetal forming agent to obtain the compound of formula(16-a). In a preferred embodiment, the starting compound of formula(7-a), or salt thereof, is according to formulae (7b) or (7c), or saltsthereof, as defined above, preferably of formula (7-b).

Preferred “thioacetal forming” agents are thiols (eg methanethiol,ethanethiol, thiophenol) or a dithiol (eg 1,2-ethanedithiol,1,3-propanedithiol). Usually the reaction is performed in the presenceof an acid, for example, a Brønsted acid (such as hydrochloric acid), aLewis acid (such as borontrifluoride or titanium tetrachloride) or asolid-supported acid (such as Amberlyst-15®). Conditions whereby theacid is generated in situ (eg dimethylsulfide-bromine complex) are alsosuitable. Preferably the acid is used in catalytic quantities. Furtherexamples of preferred “thioacetal forming” reagents are described, e.g.in relevant chapters of standard reference works such as P. G. M. Wutsand T. W. Greene, “Greene's Protective Groups in Organic Synthesis’,Fourth Edition, Wiley, New Jersey, 2007.

Section B.5.2:

In another aspect, the present invention relates to a process forpreparing a compound of formula (6), or a tautomer thereof,

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,said process comprising removal of the acetal functionality in acompound of formula (16), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, Y is oxygen andeach R9, is, independently, alkyl, aryl, arylalkyl (eg benzyl) or acetylor both R9 form together a 4 to 7, preferably a 5 to 6 membered acetalring,to obtain the compound of formula (6).

In another aspect, the present invention relates to a process forpreparing a compound of formula (6-a), or a tautomer thereof

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,said process comprising removal of the acetal functionality in acompound of formula (16-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, Y is oxygen andeach R9, is, independently, alkyl, aryl, arylalkyl (eg benzyl) or acetylor both R9 form together a 4 to 7, preferably a 5 to 6 membered acetalring,to obtain the compound of formula (6-a).

Suitable conditions for the removal of the acetal functionality includehydrolysis, e.g. the use of an acid in the presence of water. Suitableacids include Brønsted acids (such as hydrochloric acid, acetic acid,trifluoroaceteic acid, oxalic acid), Lewis acids (such as irontrichloride), sulphonic acids (such as 4-toluenesulphonic acid) orconditions that generate an acid in situ (eg iodine), as defined above.Other conditions include hydrogenation (eg Pd/C) [for e.g. arylalkyl,such as when R9 is arylakyl] or a base (such as sodium hydroxide orpotassium carbonate [for e.g. diacetylacetals, such as when R9 is anacetyl group, for example an alkylacetyl group [R9=—C(═O)alkyl] such asmethylacetyl [R9=—C(═O)CH₃]. Further examples of preferred agents forthe removal of acetal functionalities are described, e.g. in relevantchapters of standard reference works such as P. G. M. Wuts and T. W.Greene, “Greene's Protective Groups in Organic Synthesis', FourthEdition, Wiley, New Jersey, 2007.

In another aspect, the present invention relates to a process forpreparing a compound of formula (6), or a tautomer thereof,

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,said process comprising removal of the thioacetal functionality in acompound of formula (16), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, Y is sulfur andeach R9, is, independently, alkyl, aryl, arylalkyl (eg benzyl) or acetylor both R9 form together a 4 to 7, preferably a 5 to 6 memberedthioacetal ring,to obtain the compound of formula (6).

In another aspect, the present invention relates to a process forpreparing a compound of formula (6-a), or a tautomer thereof,

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,said process comprising removal of the thioacetal functionality in acompound of formula (16-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, Y is sulfur andeach R9, is, independently, alkyl, aryl, arylalkyl (eg benzyl) or acetylor both R9 form together a 4 to 7, preferably a 5 to 6 membered acetalring,to obtain the compound of formula (6-a).

This removal of the thioacetal functionality takes place preferably bytreatment with a Lewis acid or by oxidation. Lewis acids (such as silverperchlorate, iron trichloride) or oxidising agents {such as iodine,2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), peroxides,[bis(trifluoroacetoxy)iodo]benzene or alkylating agents (such as methyliodide in the presence of water) or mercury(II) salts (such as mercurydichloride, mercury perchlorate, mercury oxide)}. Further examples ofpreferred agents for removing thioacetal functionalities are described,e.g. in relevant chapters of standard reference works such as P. G. M.Wuts and T. W. Greene, “Greene's Protective Groups in OrganicSynthesis', Fourth Edition, Wiley, New Jersey, 2007.

SECTION C: CONVERSION OF A COMPOUND OF FORMULA (7) INTO A COMPOUND OFFORMULA (1) VIA A COMPOUND OF FORMULA (2)

The processes, according to the present invention, to convert of acompound of formula (7), as defined herein, into a compound of formula(1), as defined herein, are outlined in Scheme 4.

Thus, in another aspect the present invention relates to a process toconvert a compound of formula (7), as described herein, into a compoundof formula (1), as described herein, said method comprising:

-   -   a) any one of methods in Section B to convert (7) into (4),    -   b) any one of methods in Section C.1 to convert (4) into (2),        and    -   c) any one of methods in Section C.2 to convert (2) into (1).

As discussed below, Sections C.1 and C.2 as such are also preferredembodiments of the present invention.

Section C.1: Ring Opening of a Compound of Formula (4)

In another aspect, the present invention relates to a process forpreparing a compound according to formula (2),

or salt thereof,wherein R1 and R2 are, independently of each other, hydrogen or anitrogen protecting group, and R3 is a carboxyl group or an ester group,comprising reacting a compound of formula (4)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, with a lactamring opening agent to obtain the compound of formula (2).

In a preferred embodiment, a compound of formula (4-a)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, is treated with alactam ring opening agent to obtain a compound according to formula(2-a),

or salt thereof,wherein R1 and R2 are, independently of each other, hydrogen or anitrogen protecting group, and R3 is a carboxyl group or an ester group.

Examples of lactam ring opening agents are; nucleophilic bases such asalkali metal hydroxides (for example sodium hydroxide or lithiumhydroxide), neutral compounds such as hydrogenperoxides (such as lithiumhydrogenperoxide) and acids. Acids are, for example, Lewis or Brønstedacids, mineral acids such as sulphuric, perchloric and hydrochloricacid, sulphonic acids such as para-toluenesulphonic acid orpolymer-bound acids such as Amberlyst®. Preferably, hydrochloric acid isused as a lactam ring opening agent. Preferably acids are used in thepresence of water or an alcohol (such as methanol or ethanol). Thelactam ring opening agent can be used catalytically orstoichiometrically. Preferably, the lactam ring opening agent is used inan amount from 1 to 10 equivalents.

Section C.2: Reduction of a Compound of Formula (2)

The subject-matter of the present invention relates to a process forpreparing a compound according to formula (1),

or salt thereof,wherein R1 and R2 are, independently of each other, hydrogen or anitrogen protecting group, and R3 is a carboxyl group or an ester group,comprising reducing a compound according to formula (2),

or salt thereof,wherein R1 and R2 are, independently of each other, hydrogen or anitrogen protecting group, and R3 is a carboxyl group or an ester group,to obtain the compound of formula (1). In particular, R3 is a carboxylgroup, ethyl ester or methyl ester.

Preferably, a compound according to formula (2-a), or salt thereof,

wherein R1, R2 and R2 are defined as above, is used as startingcompound. If the compound (2-a), or salt thereof, is used as startingcompound, compounds according to formula (1-a)

and formula (1-b),

or salts thereof, wherein R1, R2 and R3 are defined as above, can beobtained. In a preferred embodiment R1=Boc and/or R2=H. In anotherpreferred embodiment, R3=CO₂H, or CO₂Et, or CO₂ ⁻ (carboxylate). Mostpreferably R3=CO₂H.

In particular, the group R3 of the compounds of formula (1) or (2),preferably of formula (1-a) or (2-a), is CO₂H, CO₂Et or CO₂Me.

In one embodiment, the salts of the compounds according to formula (1-a)or (1-b) are generated (e.g. R3=CO₂ ⁻) under the conditions employed inaccordance with the present invention. The salts can then be optionallyhydrolysed to give the free acid. Preferred salts are those of alkalimetals (Li, Na, K) or amines (eg diisopropylethylamine, triethylamine).

In a preferred embodiment, the reduction of the compound of formula (2),or salt thereof, preferably of formula (2-a), takes place with hydrogenin the presence of a transition metal catalyst, preferably in thepresence of a transition metal catalyst comprising an organometalliccomplex and a chiral ligand. The reduction may occur under hetereo- orhomogeneous hydrogenation conditions, preferably under homogeneoushydrogenation conditions. In one embodiment, the hetereo- or homogeneoushydrogenation takes place in the presence of a base, such as amine bases(e.g. triethylamine, iPr₂EtN or 1,4-diazabicyclo[2.2.2]octane) or alkalimetal bases (e.g. LiOH, NaOH or KOH). In one embodiment, thehetereogeneous hydrogenation takes place in the presence of an alkalimetal, in particular in an alcohol solvent (e.g. iPrOH, EtOH, MeOH); forexample KOH in ethanol. In a further embodiment, the hydrogenation, inparticular the homogeneous hydrogenation, takes place in the presence ofan acid such as methanesulfonic acid or tetrafluoroboric acid.

Generally, the hetereogeneous hydrogenation is carried out in thepresence of a transition metal catalyst, wherein the transition metal isselected from group 9 or 10 of the periodic table. Therefore, thetransition metal catalyst comprises, for example, Cobalt (Co), Rhodium(Rh), Iridium (Ir), Nickel (Ni), Palladium (Pd) and/or Platinum (Pt). Inparticular, the transition metal catalyst is Pt, Pd, or Rh on a solidsupport, such as carbon. In one embodiment the transition metal catalystis Pd on carbon.

The hetereogeneous hydrogenation is usually performed in a solvent, suchas ether solvents (eg THF), ester solvents (eg isopropyl acetate) oralcohol solvents (eg isopropanol, ethanol or methanol); in particularisopropyl acetate and ethanol.

Generally, the homogeneous hydrogenation is carried out in the presenceof a transition metal catalyst, wherein the transition metal is selectedfrom group 7, 8 or 9 of the periodic table. Therefore, the transitionmetal catalyst comprises, for example, the transition metal Manganese(Mn), Rhenium (Re), Iron (Fe), Ruthenium (Ru), Osmium (Os), Cobalt (Co),Rhodium (Rh) and/or Iridium (Ir).

In a preferred embodiment, the transition metal catalyst comprises anorganometallic complex and a chiral ligand.

The organometallic complex comprises a transition metal selected fromgroup 7, 8 or 9 of the periodic table, for example the transition metalrhodium, iridium or ruthenium in particular rhodium or ruthenium. Anorganometallic complex comprising rhodium is particularly suitable.

The organometallic complexes can comprise a single transition metalatom. In preferred embodiments the complexes can comprise two or moretransition metal atoms, optionally comprising a metal-metal bond. In apreferred embodiment two metal atoms are bridged via two halides.Generally, the organometallic complex, comprises one or more transitionmetal atoms and suitable achiral ligands.

Suitable achiral ligands for the organometallic complex generally areσ-donor ligands, σ-donor/π-acceptor ligands or σ,π-donor/π-acceptorligands. Examples for suitable achiral ligands are among others carbonmonoxide, halides (e.g. Cl, I or Br), phosphines [e.g.tricyclohexylphosphine (PCy₃)], alkenyls (e.g. cod, nbd, 2-metallyl),alkynyls, aryls (e.g. pyridine, benzene, p-cymene), carbonyls (e.g.acac, trifluoroacetate or dimethylformamide) and mixtures thereof.

Examples of preferred achiral ligands for the organometallic complexare: norbornadiene (nbd), cyclooctadiene (cod), pyridine (pyr), cymene,in particular p-cymene, and iodide.

Examples for organometallic complexes are: a ruthenium organometalliccomplex, such as [RuI₂(p-cymene)]₂, [Ru(cod)(2-metallyl)₂] or[Ru(cod)(OOCCF₃)₂]; a rhodium organometallic complex, such as[Rh(nbd)₂BF₄] or [Rh(cod)₂]BF₄; or an iridium organometallic complexsuch as [(Cy₃P)Ir(pyr)]Cl, [Ir(cod)₂]BArF or [Ir(cod)₂Cl]₂; inparticular [Ru(cod)(2-metallyl)₂], [Ru(cod)(OOCCF₃)₂] or[RuI₂(p-cymene)]₂; in particular [Rh(NBD)₂]BF₄, [Ru(COD)(OOCCF₃)₂] or[RuCl₂(p-cymene)₂].

In one embodiment the organometallic complex is[Rh(nbd)₂]BF₄{=Bis(norbornadiene)rhodium(I) tetrafluoroborate}.

In another embodiment, the organometallic complex is[RuI₂(p-cymene)]₂(=Diiodo(p-cymene)ruthenium(II) dimer):

Generally, the term “chiral ligand” comprises any ligand that issuitable to build chiral organometallic complexes and that comprises achiral centre. The transition metal catalyst comprises an organometalliccomplex and a chiral ligand. The chiral ligand comprises, for example, achiral phosphine and/or a chiral ferrocene. In particular, the chiralferrocene comprises a Cp (cyclopentadienyl) moiety which is substitutedwith a chiral group, such as a chiral amine, a chiral phosphine or achiral alkyl, for example as illustrated herein.

In a first embodiment, the reduction of the compound of formula (2-a),or salt thereof, provides a composition comprising the compoundsaccording to formulae (1-a) and (1-b), or salts thereof, wherein themolar ratio of compounds according to formula (1-a), or salts thereof,to compounds according to formula (1-b), or salts thereof, is at least55 to 45, preferably at least 80 to 20, more preferably at least 96 to4, most preferably at least 99 to 1.

In one embodiment, the transition metal catalyst comprises anorganometallic complex and a chiral ligand such as a Fenphos ligand, aJosiphos ligand, a Mandyphos ligand, a Walphos ligand, a Taniaphosligand, a Phospholane ligand, an Atropisomer ligand, a BoPhoz ligand, aQUINAPHOS ligand or mixtures thereof; in particular the chiral ligand isselected from the group consisting of Fenphos ligand, Josiphos ligand,Mandyphos ligand, Walphos ligand, Taniaphos ligand, Phospholane ligand,Atropisomer ligand or mixtures thereof.

Josiphos ligands, Walphos ligands, Taniaphos ligands, Mandyphos ligands,Fenphos ligands, Phospholane ligands, Atropisomer ligands and BoPhozligands are of the formulae:

wherein R, R′ and R″ are, for example, as described in WO2006/003196,EP-B1-612758, WO2006/017045, WO2006/117369, WO2007/116081,WO2006/075166, WO2008/101868, WO2006/117369, WO2004/099226, EP0967015,WO2004099226, EP0967015, Chem. Eur. J., 2002, 8, 843, WO2005/108409,WO2005/056568, EP1582527, U.S. Pat. No. 5,171,892, J. Am. Chem. Soc.,1991, 113, 8518, WO9315091, EP398132, EP646590, WO9521151, EP612758,EP564406, WO2002/002578, Chem. Rev., 2003, 103 (8), 3029 and referencescited therein and in particular as shown in examples herein.

wherein R8 and R9 are, for example, as described in: Boaz, N. W.;Debenham, S. D.; Mackenzie, E. B.; Large, S. E. Org. Lett. 2002, 4,2421; Boaz, N. W.; Debenham, S. D.; Large, S. E.; Moore, M. K.Tetrahedron: Asymmetry 2003, 14, 3575; Jia, X.; Li, X.; Lam, W. S.; Kok,S. H. L.; Xu, L.; Lu, G.; Yeung, C.-H.; Chan, A. S. C. Tetrahedron:Asymmetry 2004, 15, 2273 and Boaz, N. W.; Large, S. E.; Ponasik, J. A.,Jr.; Moore, M. K.; Barnette, T.; Nottingham, W. D. Org. Process Res.Dev. 2005, 9, 472; Chem: Rev., 2003, 103 (8), 3029. In particular R8 andR9 are:

-   -   R⁸=Me, R⁹=Ph (=MeBoPhoz);    -   R⁸=Me, R⁹=p-fluorophenyl (=p-fluorophenyl-MeBoPhoz);    -   R⁸=Me, R⁹=3,5-difluorophenyl (=3,5-F₂C₆H₃-MeBoPhoz);    -   R⁸=Bn, R⁹=3,5-difluorophenyl (=3,5-F₂C₆H₃-BnBoPhoz);    -   R⁸=Me, R⁹═(R)-binol {=(R)-BINOL-MeBoPhoz};    -   R⁸=Me, R⁹═(S)-binol {=(S)-BINOL-MeBoPhoz};    -   R⁸=Me, R⁹=p-CF₃-phenyl (=p-CF₃-phenyl-MeBoPhoz);    -   R⁸=Bn, R⁹=Ph (=Bn-BoPhoz);    -   R⁸=Me, R⁹=cyclohexyl (=Cy-MeBoPhoz);    -   R⁸=Me, R⁹=p-fluorophenyl (=p-F-MeBoPhoz);    -   R⁸═(S)-phenethyl, R⁹=Ph {(S)-phenethyl-BoPhoz};    -   R⁸═(R)-phenethyl, R⁹=Ph {(S)-phenethyl-BoPhoz};    -   R⁸═(S)-phenethyl, R⁹=Me {(S)-phenethyl-MeBoPhoz}; and    -   R⁸═(R)-phenethyl, R⁹=Me {(R)-phenethyl-MeBoPhoz};        wherein BINOL means 2,2′-dihydroxy-1,1′-dinaphthyl.

-   (R)—N-Methyl-N-diphenylphosphino-1-[(S)-2-diphenylphosphino)ferrocenyl]ethylamine    (=(R)MeBoPhoz)

-   (S)-N-Methyl-N-diphenylphosphino-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine    (=(S)MeBoPhoz)

-   1-(R)—N-Di(3,5-difluorophenyl)phosphine-N-benzyl-1-[(S)-diphenylphosphino]ferrocenyl]ethylamine=(R)-3,5-F₂C₆H₃-BnBoPhoz

-   1(R)-N-Dicyclohexylphosphine-N-methyl-1-[(S)-diphenylphosphino]ferrocenyl]ethylamine=(R)-Cy-MeBoPhoz

-   1-(R)—N-Diphenylphosphino-N—[(R)-1-phenylethyl]-1-[(S)-2-diphenylphosphino]ferrocenylethylamine=(R)-Phenethyl-(R)-BoPhoz

-   1-(R)—N-Diphenylphosphino-N—[(R)-1-phenylethyl]-1-[(R)-2-diphenylphosphino]ferrocenylethylamine=(R)-Phenethyl-(S)-BoPhoz

-   1-(R)—N-Di(4-fluorophenyl)phosphine-N-methyl-1-[(S)-diphenylphosphino]ferrocenyl]ethylamine=(R)-4-F—C6H4-MeBoPhoz

-   1-(R)—N-Di[(R)-1-phenylethyl]-N-methyl-1-[(S)-diphenylphosphino]ferrocenyl]ethylamine=(R)-Phenethyl-(R)-MeBoPhoz

-   1-(R)—N—[(R)-2,2′-Dihydroxy-1,1′-dinaphthyl]-N-methyl-1-[(S)-diphenylphosphino]ferrocenyl]ethylamine=(R)-BINOL-(R)-MeBoPhoz

-   1-(R)—N—[(S)-2,2′-Dihydroxy-1,1′-dinaphthyl]-N-methyl-1-[(S)-diphenylphosphino]ferrocenyl]ethylamine=(S)-BINOL-(R)-MeBoPhoz

-   1-(R)—N-Di(4-fluorophenyl)phosphine-N-methyl-1-[(S)-diphenylphosphino]ferrocenyl]ethylamine=(R)-p-F-MeBoPhoz

QuinaPhos ligands are of the formula:

wherein R and R′ are, for example, as described in G. Franciò, F.Faraone, W. Leitner, Angew. Chem. Int. Ed., 39, 1428 (2000), 39, 1428;Chem. Rev., 2003, 103 (8), 3029, for example R is Ph and R′ is naphthyl.In particular, suitable. QuinaPhos ligands are, for example,(R_(a),S_(c))-1Np-QUINAPHOS or (S_(a),R_(c))-1Np-QUINAPHOS.

Examples of suitable chiral ligands are:

Examples of Mandyphos ligands:

-   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene    (=Mandyphos SL-M001-1)-   (αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(dicyclohexylphosphino)ferrocene    (=Mandyphos SL-M002-1)-   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis-[di(bis-(3,5-trifluoromethyl)phenyl)-phosphino]ferrocene    (=Mandyphos SL-M003-1)-   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene    (=Mandyphos SL-M004-1)-   (αS,αS)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene    (=Mandyphos SL-M004-2)-   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethylphenyl)phosphino]ferrocene    (=Mandyphos SL-M009-1)-   (1R,1′R)-1,1′-Bis[bis(3,5-tert-butyl-4-methoxyphenyl)phosphino]-2,2′-bis[(R)-(dimethylamino)phenylmethyl]ferrocene    (=Mandyphos SL-M010-1)-   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di-(2-methylphenyl)phosphino]-ferrocene    (=Mandyphos SL-M012-1)

Examples of Josiphos ligands:

-   (R)-1-[(S)-2-Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine    (=Josiphos SL-J002-1)-   (R)-1-[(S)-2-Dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine    (=Josiphos SL-J003-1)-   (R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5-xylyl)phosphine    (=Josiphos SL-J005-1)-   (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5-xylyl)phosphine    (=Josiphos SL-J005-2)-   (R)-1-[(S)-2-Di-(3,5-bis(trifluoromethyl)phenyl)-phosphino)ferrocenyl]ethyldicyclohexylphosphine    (=Josiphos SL-J006-1)-   (S)-1-[(S)-2-Di-(3,5-bis(trifluoromethyl)phenyl)-phosphino)ferrocenyl]ethyldicyclohexylphosphine    (=Josiphos SL-J006-2)-   (R)-1-[(S)-2-Di-(3,5-bis(trifluoromethyl)phenyl)-phosphino)ferrocenyl]ethyldi(3,5-dimethylphenyl)phosphine    (=Josiphos SL-J008-1)-   (R)-1-[(S)-2-Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine    (=Josiphos SL-J009-1)-   (R)-1-[(S)-2-Di(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert.-butylphosphine    (=Josiphos SL-J011-1)-   (R)-1-[(S_(P))-2-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine    (=Josiphos SL-J013-1)-   (R)-1-[(S)-2-bis(2-methylphenyl)phosphino)ferrocenyl]ethyl    di(tert-butyl)-phosphine (=Josiphos SL-J211-1)-   (R)-1-[(S)-2-diethylphosphino)ferrocenyl]ethyl    di(tert-butyl)-phosphine (=Josiphos SL-J301-1)-   (R)-1-[(S)-2-Di-ethylphosphino)ferrocenyl]ethyldi-(2-methylphenyl)phosphine(=Josiphos    SL-J302-1)-   (R)-1-[(S)-2-bis(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyl    bis(4-trifluoromethyl)-phosphine (=Josiphos SL-J403-1)-   (R)-1-[(S)-2-bis(3,5-dimethylphenyl)phosphino)ferrocenyl]ethyl    bis(3,5-dimethylphenyl)-phosphine (=Josiphos SL-J408-1)-   (R)-1-[(S)-2-bis(3,5-dimethylphenyl)phosphino)ferrocenyl]ethyl    bis[bis-(3,5-trifluoro-methyl)phenyl]-phosphine (=Josiphos    SL-J412-1)-   (R)-1-[(S)-2-bis(2-methoxyphenyl)phosphino)ferrocenyl]ethyl    bis(2-methoxyphenyl)-phosphine (=Josiphos SL-J430-1)-   (R)-1-[(S)-2-bis(2-isopropoxyphenyl)phosphino)ferrocenyl]ethyl    bis(3,5-dimethylphenyl)-phosphine (=Josiphos SL-J431-1)-   (R)-1-[(S)-2-di(tert-butyl)phosphino)ferrocenyl]ethyl    bis(3,5-dimethylphenyl)-phosphine (=Josiphos SL-J501-1)-   (R)-1-[(S)-2-diethylphosphino)ferrocenyl]ethyl    bis(2-methylphenyl)-phosphine (=Josiphos SL-J503-1)-   (R)-1-[(S)-2-cyclohexylphosphino)ferrocenyl]ethyl    bis(2-methylphenyl)-phosphine (=Josiphos SL-J504-1)-   (S)-1-[(R)-2-cyclohexylphosphino)ferrocenyl]ethyl    bis(2-methylphenyl)-phosphine (=Josiphos SL-J504-2)-   (R)-1-[(S)-2-Di-tert.-butylphosphino)ferrocenyl]ethyldicyclohexylphosphine    (=Josiphos SL-J505-1)-   (S)-1-[(R)-2-di(tert-butyl)phosphino)ferrocenyl]ethyl    bis(2-methylphenyl)-phosphine (=Josiphos SL-J505-2)-   (R)-1-[(S)-2-di(tert-butyl)phosphino)ferrocenyl]ethyl    bis(4-trifluoromethyl)-phosphine (=Josiphos SL-J506-1)

Examples of Walphos ligands:

-   (R)-1-[(R)-2-(2.-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine    (=Walphos SL-WO01-1)-   (S)-1-[(S)-2-(2.-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine    (=Walphos SL-WO01-2)-   (R)-1-[(R)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldicyclohexylphosphine    (=Walphos SL-WO03-1)-   (R)-1-[(R)-2-{2′-Di(3,5-dimethyl-4-methoxyphenyl)-phosphinophenyl}ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine    (=Walphos SL-WO05-1)-   (R)-1-[(R)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi(3,5-xylyl)phosphine    (=Walphos SL-WO06-1)-   (R)-1-[(R)-2-(2′-Dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-(3,5-trifluoromethyl)-phenyl)-phosphine    (=Walphos SL-WO08-1)-   (S)-1-[(S)-2-(2′-Dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-(3,5-trifluoromethyl)-phenyl)-phosphine    (=Walphos SL-WO08-2)-   (R)-1-[(R)-2-(2.-Di-(3,5-xylyl)    phosphinophenyl)-ferrocenyl]ethyldi(3,5-xylyl)phosphine (=Walphos    SL-WO09-1)-   (R)-1-[(R)-2-(2′-(Diphenylphosphinophenyl)ferrocenyl]ethyl    di(tert-butyl)-phosphine (=Walphos SL-WO12-1)-   (R)-1-{(R)-2-[4′,5′-dimethoxy-2′-(Diphenylphosphino)phenyl]ferrocenyl]ethyl    di(bis-(3,5-trifluoromethyl)phenyl)-phosphine (=Walphos SL-WO21-1)-   (R)-1-{(R)-2-[2′-bis(2-methoxyphenyl)phosphinophenyl]ferrocenyl]ethyl    di(bis-(3,5-trifluoro-methyl)phenyl)-phosphine (=Walphos SL-WO24-1)

Examples of Fenphos ligands:

-   (R)—(S)-1-(Dimethylamino-eth-1-yl)-2-difurylphosphino-3-diphenylphosphino-ferrocene    (=Fenphos SL-F055-1)-   (R)—(S)-1-(Dimethylamino-eth-1-yl)-2-diethylphosphino-3-bis(2-Methoxyphenyl)-phosphino-ferrocene    (=Fenphos SL-F056-1)-   (R)—(S)-1-(Dimethylamino-eth-1-yl)-2-bis(3,5-dimethyl-4-methoxyphenyl)phosphino-3-dicyclohexylphosphino-ferrocene    (=Fenphos SL-F061-1)-   (R)—(S)-1-(Dimethylamino-eth-1-yl)-2-bis(4-trifluoromethylphenyl)phosphino-3-dicyclohexylphosphino-ferrocene    (=Fenphos SL-F062-1)-   (Rc)-(Sp)-(Se)-1,1′-Bis[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]phenylphosphino    ferrocene (=Fenphos SL-F131-1)-   (Rc)-(Sp)-(Se)-1{[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]phenylphosphino}-2-{[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]isopropylphosphino}ferrocene    (=Fenphos SL-F132-1)-   (Rc)-(Sp)-(Se)-1-{[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]phenyl    phosphino}-2{[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]cyclohexylphosphino}ferrocene    (=Fenphos SL-F133-1)-   (Rc)-(Sp)-(Se)-1,1′-Bis[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]cyclohexyl    phosphino ferrocene (=Fenphos SL-F134-1)-   (Rc)-(Sp)-(Se)-1,1′-Bis[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]isopropyl    phosphino ferrocene (=Fenphos SL-F135-1)-   (Rc)-(Sp)-(Se)-1-{[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]phenylphosphino}-1′{di[bis-(3,5-trifluoromethyl)phenyl]-phosphino}    ferrocene (=Fenphos SL-F355-1)-   (Rc)-(Sp)-(Se)-1{[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]phenylphosphino}-1′-(dicyclohexylphosphino)    ferrocene (=Fenphos SL-F356-1)-   (Rc)-(Sp)-(Se)-1{[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]cyclohexylphosphino}-1′-(dicyclohexylphosphino)    ferrocene (=Fenphos SL-F365-1)

Examples of Atropisomer ligands:

-   (R)-(+)-(6,6i-Dimethoxybiphenyl-2,2′-diyl)-bis(diphenylphosphine)    (=Atropisomer SL-A101-1)-   (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine)    (=Atropisomer SL-A109-2)-   (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diisopropylphosphine)    (=Atropisomer SL-A116-2)-   (R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(dicycylobutylphosphine)    (=Atropisomer SL-A118-1)

Examples of Taniaphos ligands:

-   (1S)-Diphenylphosphino-2-[(R)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)-methyl]ferrocene    (=Taniaphos SL-T001-1)-   (1R)-Diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)-methyl]ferrocene    (=Taniaphos SL-T001-2)-   (R)-1-bis(4-methoxy-3,5-dimethylphenyl)phosphino-2-{(R)-(dimethylamino)₄₂-(bis(4-methoxy-3,5-dimethylphenyl)phosphino)phenyl]methy}ferrocene    (=Taniaphos SL-T003-1)-   (S)-1-diphenylphosphino-2-[(S)-hydroxy-[2-(diphenylphosphino)phenyl]methyl]ferrocene    (=Taniaphos SL-T021-2)

Examples of phospholane ligands:

-   2-[(2′,5′R)-2′,5′-dimethylphospholano]-1-[(R)-diphenylphosphino]ferrocene    (=Phospholane SL-P051-1)-   1,2-Bis[(2S,5S)-2,5-dimethylphospholano]ethane (=Phospholane    SL-P104-2)-   1,2-Bis[(2R,5R)-2,5-diethylphospholano]benzene (=Phospholane    SL-P102-1)-   (R,R,R,R)-2,3-Bis(2,5-dimethyl-phospholanyl)benzo[b]thiophene    (=Phospholane SL-P005-1)

Examples for further suitable chiral ligands are:

-   (S)-(6,6′-Dimethylbiphenyl-2,2′-diyl)bis(dicyclohexylphosphine)    (=Atropisomer SL-A132-2).

A further suitable ligand is a BDPP ligand as define herein below, inparticular (S,S)-BDPP.

The preparation of ligand (S)—C4-TunaPhos is described in J. Org. Chem.,2000, 65, 6223 (Example 4). Ligand (R)-(+)-BINAP can be purchased fromcommercial sources such as Aldrich. BoPhoz and QUINAPHOS ligands arecommercially available from Johnson Matthey plc (London, UnitedKingdom). All other above-mentioned ligands (Mandyphos, Josiphos,Walphos, etc.) are commercially available from Solvias AG (Basel,Switzerland).

In particular, suitable chiral ligands are, for example:

SL-M004-1, SL-M004-2, SL-M002-1, SL-M003-1, SL-M009-1, SL-M0010-1,SL-M012-1, SL-J005-1, SL-J505-1, SL-J005-2, SL-J008-1, SL-J009-1,SL-J013-1, SL-J211-1, SL-J301-1, SL-J403-1, SL-J408-1, SL-J412-1,SL-J430-1, SL-J431-1, SL-J501-1, SL-J503-1, SL-J504-1, SL-J505-2,SL-J506-1, SL-F131-1, SL-F132-1, SL-F133-1, SL-F134-1, SL-F135-1,SL-F355-1, SL-F356-1, SL-F365-1, SL-T001-1, SL-T001-2, SL-T003-1,SL-T021-2, (S,S′)-BDPP, (R)-MeBoPhoz, (S)-MeBoPhoz,(R)-3,5-F₂C₆H₃-BnBoPhoz, (R)-Cy-MeBoPhoz, (R)-Phenethyl-(R)-BoPhoz,(R)-Phenethyl-(S)-BoPhoz, SL-WO01-1, SL-WO05-1, SL-WO09-1, SL-WO12-1,SL-WO24-1, SL-WO08-1, SL-A101-1, SL-A109-1, SL-A109-2, SL-A118-1,SL-A116-2, SL-A132-2, SL-P102-1, SL-P005-1, SL-P104-2,(R_(a),S_(c))1Np-QUINAPHOS} and/or (S_(a),R_(c))1Np-QUINAPHOS},

Particularly suitable chiral ligands are, for example:

(R)-Cy-MeBoPhoz; (R)-Phenethyl-(S)-BoPhoz; SL-A101-1; SL-A109-2;SL-A116-2; SL-A118-1; SL-A132-2; SL-F131-1; SL-F132-1; SL-F133-1;SL-F134-1; SL-F135-1; SL-F355-1; SL-F356-1; SL-F365-1; SL-J005-2;SL-J505-1; SL-J008-1; SL-J013-1; SL-J301-1; SL-J403-1; SL-J408-1;SL-J430-1; SL-J431-1; SL-J501-1; SL-J504-1; SL-J504-2; SL-J505-2;SL-J506-1; SL-M002-1; SL-M003-1; SL-M004-1; SL-M009-1; SL-M010-1;SL-P051-1; SL-T001-1; SL-T001-2; SL-T003-1; SL-T021-2; (S,S)-BDPP;SL-WO01-1; SL-WO05-1; SL-WO08-1; SL-WO08-2; SL-WO09-1; SL-WO12-1;SL-WO21-1; and/or SL-WO24-1.

Further particularly suitable ligands are, for example:

SL-A101-1; SL-F131-1; SL-F132-1; SL-F356-1; SL-J505-1; SL-J008-1;SL-J504-2; SL-J505-2; SL-M010-1; SL-P051-1; (S,S)-BDPP; SL-WO01-1;SL-WO05-1; SL-WO08-1; SL-WO09-1; SL-WO12-1; SL-WO21-1

Suitable combinations of organometallic complex and chiral ligand are,for example:

-   -   rhodium organometallic complex and a Fenphos, Walphos, Josiphos        or a Phospholane ligand; in particular [Rh(nbd)₂]BF₄ and a        Fenphos, Walphos, Josiphos or a PhanePhos ligand; such as        Rh(nbd)₂]BF₄ and SL-WO05-1, SL-WO08-1, SL-F356-1, SL-J008-1,        SL-P051-1, SL-WO09-1, SL-WO01-1, SL-WO12-1, SL-WO21-1, SL-J505-2        or SL-J504-2; in particular, Rh(nbd)₂]BF₄ and SL-WO08-1,        SL-J008-1, SL-P051-1, SL-J505-2 or SL-J504-2;    -   ruthenium organometallic complex and an Atropisomer, Mandyphos        or a Fenphos ligand; in particular [RuI₂(p-cymene)]₂,        [Ru(cod)(2-metallyl)₂] or [Ru(cod)(OOCCF₃)₂] and an Atropisomer,        Mandyphos, BDPP, Josiphos or a Fenphos ligand; such as        [RuI₂(p-cymene)]₂, [Ru(cod)(2-metallyl)₂] or [Ru(cod)(OOCCF₃)₂]        and SL-A101-1, SL-M010-1, (S,S)-BDPP, SL-J505-1, SL-F131-1,        SL-F132-1 or SL-F134-1; or    -   iridium organometallic complex and a Fenphos, Walphos or        Josiphos ligand; in particular [Ir(cod)Cl]₂ and a Fenphos,        Walphos or Josiphos ligand; such as [Ir(cod)Cl]₂ and SL-F356-1,        SL-WO24-1 or SL-J504-1.

When using these combinations, the reduction of the compound of formula(2-a), or salt thereof, provides a composition comprising the compoundsaccording to formulae (1-a) and (1-b), or salts thereof, wherein themolar ratio of compounds according to formula (1-a), or salts thereof,to compounds according to formula (1-b), or salts thereof, is at least55 to 45, preferably at least 80 to 20, more preferably at least 96 to4, most preferably at least 99 to 1.

In a second embodiment, the reduction of the compound of formula (2-a),or salt thereof, provides a composition comprising the compoundsaccording to formulae (1-a) and (1-b), or salts thereof, wherein themolar ratio of compounds according to formula (1-b), or salts thereof,to compounds according to formula (1-a), or salts thereof, is at least55 to 45, preferably at least 80 to 20, more preferably at least 91 to9.

In one embodiment, the transition metal catalyst comprises anorganometallic complex and a chiral ligand such as a Fenphos ligand, aJosiphos ligand, a Mandyphos ligand, a Walphos ligand, a Taniaphosligand, a Phospholane, an Atropisomer ligand, a BoPhoz ligand, aQUINAPHOS ligand or mixtures thereof; in particular the chiral ligand isselected from the group consisting of Josiphos ligand, Mandyphos ligand,Walphos ligand, Taniaphos ligand, Atropisomer ligand, QUINAPHOS ligandor mixtures thereof.

Suitable chiral ligands are, for example:

SL-A132-2, SL-WO08-2, SL-A109-2, SL-A109-2, SL-T021-2, SL-T003-1,SL-M003-1, SL-A101-1, SL-J002-1, SL-J504-1, SL-T001-1, SL-J501-1,SL-WO08-1, SL-J301-1, SL-F356-1, SL-M004-2, SL-M012-1, SL-J013-1,SL-J211-1, SL-WO09-1, SL-J412-1, SL-WO12-1, SL-J009-1, SL-J503-1,SL-J506-1, SL-J431-1, SL-J430-1 or (R_(a),S_(c))1Np-QUINAPHOS; inparticular SL-WO08-2, SL-J504-1, SL-WO09-1, SL-J412-1, SL-J503-1

Combinations of organometallic complex and chiral ligand are forexample:

-   -   rhodium organometallic complex and an Atropisomer, Walphos,        Taniaphos, Josiphos, Mandyphos or Quinaphos ligand; such as        [Rh(nbd)₂]BF₄ or [Rh(cod)2]BF4 and an Atropisomer, Walphos,        Taniaphos, Josiphos, Mandyphos or a Quinaphos ligand; in        particular [Rh(nbd)₂]BF₄ and SL-WO08-2, SL-J504-1, SL-WO09-1,        SL-J41201 or SL-J503-1;    -   ruthenium organometallic complex and an Atropisomer, Taniaphos,        Mandyphos, Walphos, Josiphos or Fenphos ligand; such as        [RuI₂(p-cymene)]₂, [Ru(cod)(2-metallyl)₂], [RuI₂(p-cymene)]₂ or        [Ru(cod)(OOCCF₃)₂] and an Atropisomer, Taniaphos, Mandyphos,        Walphos, Josiphos or Fenphos ligand. Even more preferably,        [RuI₂(p-cymene)]₂, [Ru(cod)(2-metallyl)₂], [RuI₂(p-cymene)]₂ or        [Ru(cod)(OOCCF₃)₂] and SL-A109-2, SL-T021-2, SL-M003-1,        SL-WO08-1, SL-J301-1, SL-F356-1, SL-M004-2, SL-M012-1,        SL-J002-1, SL-J013-1, SL-J211 or SL-J503-1; or    -   iridium organometallic complex and a Walphos or Josiphos ligand;        in particular [Ir(cod)Cl]₂ and a Walphos or Josiphos ligand;        such as [Ir(cod)Cl]₂ and SL-WO09-1, SL-WO12-1 or SL-J009-1.

When using these combinations, the reduction of the compound of formula(2-a), or salt thereof, provides a composition comprising the compoundsaccording to formulae (1-a) and (1-b), or salts thereof, wherein themolar ratio of compounds according to formula (1-b), or salts thereof,to compounds according to formula (1-a), or salts thereof, is at least55 to 45, preferably at least 80 to 20, more preferably at least 91 to9.

In a third embodiment, the reduction of the compound of formula (2-a),or salt thereof, provides a composition comprising the compoundsaccording to formulae (1-a) and (1-b), or salts thereof, wherein themolar ratio of compounds according to formula (1-a), or salts thereof,to compounds according to formula (1-b), or salts thereof, is at least55 to 45, preferably at least 80 to 20, more preferably at least 97 to3, most preferably at least 99 to 1.

In one embodiment, the transition metal catalyst comprises a transitionmetal selected from the group 8 or 9, such as rhodium, ruthenium oriridium and a chiral ligand selected from the group consisting of BoPhozligand, BINAP ligand, BINOL ligand, a Phospholane ligand, PhanePhosligand, P-Phos ligand, QuinaPhos ligand, ProPhos ligand, BDPP ligand,DIOP ligand, DIPAMP ligand, DuanPhos ligand, Nor Phos ligand, BINAMligand, CatAsium ligand, SimplePHOX ligand, PHOX ligand, ChiraPhosligand, Ferrotane ligand, BPE ligand, TangPhos ligand, JafaPhos ligand,DuPhos ligand, Binaphane ligand and mixtures thereof.

BoPhoz ligands are of the formula described above, in particular(R)-4-F—C₆H₄-MeBoPhoz, (R)-BINOL-(R)-MeBoPhoz, (R)-MeBoPhoz,(R)-p-F-MeBoPhoz, (R)-Phenethyl-(R)-MeBoPhoz, (S)-BINOL-(R)-MeBoPhoz or(S)-MeBoPhoz.

QUINAPHOS ligands are of the formula described above, in particular(R_(a),S_(c))-1Np-QUINAPHOS or (S_(a),R_(c))-1Np-QUINAPHOS.

-   (S)-2-(1-Naphthyl)-8-diphenylphosphino-1-(R)-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a]dinaphthalen-4-yl)-1,2-dihydroquinoline=(R_(a),S_(c))-1Np-QUINAPHOS-   (R)-2-(1-Naphthyl)-8-diphenylphosphino-1-(S)-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)-1,2-dihydroquinoline=(S_(a),R_(c))-1Np-QUINAPHOS

BINAP ligands are of the formula:

wherein R is, for example, as described in R. Noyori, H. Takaya, Acc.Chem. Res., 23 345 (1990), for example R is phenyl (=BINAP) or tolyl(=Tol-BINAP). In particular, suitable BINAP ligands are (R)-BINAP,(R)-Tol-BINAP, (S)-BINAP or (S)-Tol-BINAP.(R)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binapthalene=(R)-Tol-BI NAP(S)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binapthalene=(S)-Tol-BINAP(R)-2,2′-Bis(diphenylphosphino)-1,1′-binapthalene=(R)-BINAP(S)-2,2′-Bis(diphenylphosphino)-1,1′-binapthalene=(S)-BINAP

BINOL ligands are of the formula:

wherein R is, for example, as described in Noyori, R.; Tomino, I.;Tanimoto, Y.; Nishizawa, M. J. Am. Chem. Soc, 106, 6709 (1984); Noyori,R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc., 106, 6717(1984), for example is phenyl (=BINOL). In particular, suitable BINOLligands are, for example, (R)-BINOL or (S)-BINOL.

PhanePhos ligands are of the formula:

wherein Ar is, for example, as described in K. Rossen, P. J. Pye, R. A.Reamer, N. N. Tsou, R. P. Volante, P. J. Reider J. Am. Chem. Soc. 119,6207 (1997), for example Ar is Ph (=PhanePhos), 4-Me-C₆H₄(=Tol-PhanePhos), 4-MeO—C₆H₄ (An-PhanePhos), 3,5-Me₂-C₆H₃(=Xyl-Phanephos) or 3,5-Me₂-4-MeO—C₆H₂ (=MeO-Xyl-Phanephos). Inparticular, suitable PhanePhos ligands are, for example, (R)-PhanePhos,(R)-Xyl-PhanePhos, (S)-Xyl-PhanePhos, (S)-PhanePhos, (R)-An-PhanePhos,(R)-MeO-Xyl-PhanePhos or (R)-Tol-PhanePhos.

-   (R)-4,12-Bis(diphenylphosphino)[2.2]-paracyclopentane=(R)-PhanePhos-   (S)-4,12-Bis(diphenylphosphino)[2.2]-paracyclopentane=(S)-PhanePhos-   (R)-4,12-Bis(di(3,5-xylyl)phosphino)[2.2]-paracyclopentane=(R)-Xyl-PhanePhos-   (S)-4,12-Bis(di(3,5-xylyl)phosphino)[2.2]-paracyclopentane=(S)-Xyl-PhanePhos-   (R)-4,12-Bis(di(p-tolyll)phosphino)-[2.2]-paracyclopentane=(R)-Tol-PhanePhos-   (R)-4,12-Bis(di(p-methoxyphenyl)phosphino)-2.2]-paracyclopentane=(R)-An-PhanePhos-   (R)-4,12-Bis(di(p-methoxy-3,5-dimethylphenyl)phosphino)-[2.2]-paracyclopentane=(R)-MeO-Xyl-PhanePhos

P-Phos ligands are of the formula:

wherein Ar is, for example, as described in C.-C. Pai, C.-W. Lin, C.-C.Lin, C.-C. Chen, A. S. C. Chan, W. T. Wong, J. Am. Chem. Soc. 122, 11513(2000), for example Ar is Ph (=P-Phos), 4-Me-C₆H₄ (=Tol-P-Phos),4-MeO—C₆H₄ (An-P-Phos), 3,5-Me₂-C₆H₃ (=Xyl-P-Phos) or 3,5-Me₂-4-MeO-C₆H₂(=MeO-Xyl-P-Phos). In particular, suitable P-Phos ligands are, forexample, (R)—P-Phos, (R)-Xyl-P-Phos, (S)—P-Phos or (S)-Xyl-P-Phos.

-   (R)-2,2′,6,6′-Tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyridine=(R)—P-Phos-   (S)-2,2′,6,6′-Tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyridine=(S)—P-Phos-   (R)-2,2′,6,6′-Tetramethoxy-4,4′-bis(di(3,5-xylyl)phosphino)-3,3′-bipyridine=(R)-Xyl-P-Phos-   (S)-2,2′,6,6′-Tetramethoxy-4,4′-bis(di(3,5-xylyl)phosphino)-3,3′-bipyridine=(S)-Xyl-P-Phos

ProPhos ligands are of the formula:

wherein R and R′ are, for example, as described in Fryzuk, M. D.;Bosnich, B. J. Am. Chem. Soc., 100, 5491 (1978), for example R′ is Meand R is Ph. In particular, a suitable ProPhos ligands is, for example,(R)-ProPhos.

(R)-1,2-Bis(diphenylphosphino)propane=(R)-ProPhos

BDPP ligands are of the formula:

wherein R is, for example, as described in Bakos, J.; Toth, I.; Marko',L. J. Org. Chem., 46, 5427 (1981), for example R is Ph. In particular,suitable BDPP ligands are, for example, (R,R)-BDPP or (S,S)-BDPP.

-   (2R,4R)-2,4-Bis(diphenylphosphino)pentane=(R,R)-BDPP-   (2S,4S)-2,4-Bis(diphenylphosphino)pentane=(S,S)-BDPP

DIOP ligands are of the formula:

wherein R is, for example, as described in Kagan, H. B.; Dang, T. P.Chem. Commun. 1971, 481; Kagan, H. B.; Dang, T. P. J. Am. Chem. Soc.,94, 6429 (1972), for example R is Ph. In particular, suitable DIOPligands are, for example, (S,S)-DIOP or (R,R)-DIOP.

-   (4R,5R)-4,5-Bis(diphenylphosphino-methyl)-2,2-dimethyl-1,3-dioxolane=(R,R)-DIOP-   (4S,5S)-4,5-Bis(diphenylphosphino-methyl)-2,2-dimethyl-1,3-dioxolane=(S,S)-DIOP

DIPAMP ligands are of the formula:

wherein R and R′ are, for example, as described in Knowles, W. S. Acc.Chem. Res. 16, 106 (1983), for example R is Ph and R′ is Anisyl. Inparticular, a suitable DIPAMP ligand is, for example, (R,R)-DIPAMP.

(R,R)-1,2-Ethanediylbis[(2-methoxyphenyl)phenylphosphine]=(R,R)-DIPAMP

DuanPhos ligands are of the formula:

wherein R is, for example, as described in PCT/US02/35788, for example Ris tert-butyl. In particular, a suitable DuanPhos ligand is, forexample, (R,R)-DuanPhos.

-   (1R,1R,2S,2′S)-2,2′-Di-tert-butyl-2,3,2′,3′-tetrahydro-1H,1′H-(1,1′)biisophosphindolyl=(R,R)-DuanPhos

Nor Phos ligands are of the formula:

wherein R is, for example, as described in Brunner, H.; Pieronczyk, W.;Schoenhammer, B.; Streng, K.; Bernal, I.; Korp, J. Chem. Ber. 114, 1137(1981), for example R is Ph. In particular, suitable Nor Phos ligandsare, for example, (R,R)-NorPhos or (S,S)-NorPhos.

-   (2R,3R)-2,3-Bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene=(R,R)-NorPhos-   (2S,3S)-2,3-Bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene=(S,S)-NorPhos

BINAM ligands are of the formula:

wherein R is, for example, as described in F.-Y. Zhang, C.-C. Pai, A. S.C. Chan J. Am. Chem. Soc. 120, 5808 (1998), for example R is PR′₂,wherein R′ for example is Ph. In particular, suitable BINAM ligands are,for example, (R)-BINAM-P or (S)-BINAM-P.

-   (R)—NN-Bis(diphenylphosphino)-1,1′-binaphthyl-2,2′-diamine=(R)-BINAM-P-   (S)—N,N′-Bis(diphenylphosphino)-1,1′-binaphthyl-2,2′-diamine=(S)-BINAM-P

CatASium ligands are of the formula:

wherein R, R′ and R″ are, for example, as described in Holz, J.;Monsees, A.; Jiao, H.; You, J.; Komarov, I. V.; Fischer, C.; Drauz, K.;Börner, A. J. Org. Chem., 68, 1701-1707 (2003); Holz, J.; Zayas, O.;Jiao, H.; Baumann, W.; Spannenberg, A.; Monsees, A.; Riermeier, T. H.;Almena, J.; Kadyrov, R.; Boörner, A. Chem. Eur. J, 12, 5001-5013 (2006),for example, R is Me, R′ is Ph, R″ is benzyl and G is O, NMe,N(Me)N(Me). In particular, suitable CatAsium ligands are, for example,(R)-CatASium M, (S)-CatASium M, (R)-CatASium MN, (S)-CatASium MN,(R)-CatASium D or (R)-CatASium MNN.

-   N-Benzyl-(3R,4R)-bis(diphenylphosphino)pyrrolidine=(R)-CatASium D-   2,3-Bis[(2R,5R)-2,5-dimethylphospholano]maleic    anhydride=(R)-CatASium M-   2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N-methylmaleimide=(R)-CatASium    MN-   4,5-Bis[(2R,5R)-2,5-dimethylphospholano]-1,2-dihydro-1,2-dimethyl-3,6-pyridazinedione=(R)-CatASium    MNN-   2,3-Bis[(2S,5S)-2,5-dimethylphospholano]maleic    anhydride=(S)-CatASium M-   2,3-Bis[(2S,5S)-2,5-dimethylphospholano]-N-methylmaleimide=(S)-CatASium    MN

SimplePHOX ligands are of the formula:

wherein R and R′ are, for example, as described in S. Smidt, F. Menges,A. Pfaltz, Org. Lett. 6, 2023 (2004), for example R is Cyclohexyl and R′is tert-butyl. In particular, a suitable SimplePHOX ligand is, forexample, (S)-Cy-tBu-SimplePHOX.

-   (S)-4-tert-butyl-2-(2-(dicyclohexylphosphinooxy)propan-2-yl)-4,5-dihydrooxazole=(S)-Cy-tBu-SimplePHOX

PHOX ligands are of the formula:

wherein R and R′ are, for example, as described in A. Lightfoot, P.Schnider, A. Pfaltz, Angew. Chem. In. Ed., 37, 2897 (1998), for exampleR is Ph and R′ is iPr. In particular, a suitable PHOX ligand is, forexample (S)-iPr-PHOX.

-   (S)-4-tert-Butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline=(S)-iPr-PHOX

ChiraPhos ligands are of the formula:

wherein R is, for example, as described in Fryzuk, M. B.; Bosnich, B. J.Am. Chem. Soc, 99, 6262 (1977); Fryzuk, M. B.; Bosnich, B. J. Am. Chem.Soc, 101, 3043 (1979), for example R is Ph. In particular, a suitableChiraPhos ligand is, for example, (S,S)-ChiraPhos.

-   (2S,3S)-(−)-Bis(diphenylphosphino)butane=(S,S)-Chiraphos

Ferrotane ligands are of the formula:

wherein R is, for example, as described in Berens, U.; Burk, M. J.;Gerlach, A.; Hems, W. Angew. Chem., Int. Ed. Engl. 2000, 39, 1981(2000)., for example R is methyl or ethyl, preferably ethyl. Inparticular, a suitable ferrotane ligand is, for example,(S,S)-Et-Ferrotane.

-   1,1′-Bis[(2S,4S)-2,4-diethylphosphotano)ferrocene=(S,S)-Et-Ferrotane

BPE ligands are of the formula:

wherein R is, for example, as described in Burk, M. J. Acc. Chem. Res,33, 363 (2000), for example R is Me or Ph In particular, suitable BPEligands are, for example, (S,S)-Me-BPE or (S,S)-Ph-BPE.

-   ,2-Bis[(2S,5S)-2,5-dimethylphospholano]ethane=(S,S)-Me-BPE-   ,2-Bis[(2S,5S)-2,5-diphenylphospholano]ethane=(S,S)-Ph-BPE

TangPhos ligands are of the formula:

wherein R is, for example, as described in Tang, W.; Zhang, X. Angew.Chem., Int. Ed. Engl, 41, 1612 (2002), for example R is tert-butyl. Inparticular, a suitable TangPhos ligand is, for example,(S,S,R,R)-TangPhos.

-   (1S,1S′,2R,2R′)-1,1′-Di-tert-butyl-(2,2)-diphospholane=(S,S,R,R)-TangPhos

JafaPhos ligands are of the formula:

wherein R and R′ are, for example, as described in Jendralla, H.;Paulus, E. Synlett (E. J. Corey Special Issue) 1997, 471., for example Ris Ph and R′ is isopropyl. In particular, a suitable JafaPhos ligand is,for example, (R)-JafaPhos.

-   [(R)-1,1′-Bis(diphenylphosphino)-2,2′-bis(N,N-diisopropylamido)ferrocene]=(R)-JafaPhos

DuPhos ligands are of the formula:

wherein R is, for example, as described in Burk, M. J. Acc. Chem. Res,33, 363 (2000), for example R is Me. In particular, a suitable DuPhosligand is, for example, (R)-MeDuPhos.

-   1,2-Bis[(2R,5R)-2,5-dimethylphospholano]benzene=(R)-MeDuPhos

Binaphane ligands are of formula:

for example as described in Xiao D, Zhang Z, Zhang X., Org. Lett. 1999Nov. 18; 1(10):1679. In particular, a suitable Binaphane ligand is, forexample, (R)-Binaphane.

-   (R,R)-1,2-Bis[(R)-4,5-dihydro-3H-binaphtho(1,2-c:2′,1′-e)phosphepino]benzene=(R)-Binaphane

Further suitable chiral ligands and chiral groups are given, forexample, in Tang, W and Zhang, X, Chem. Rev., 2003, 103 (8), 3029 andreferences cited therein.

The ligands above-mentioned are commercially available from JohnsonMatthey plc (London, United Kingdom) and/or from Solvias AG (Basel,Switzerland).

In one embodiment, the transition metal catalyst comprises, for example:

-   -   the transition metal rhodium and a chiral ligand such as a        P-Phos, a PhanePhos, a Phospholane, a BoPhoz, a DIOP, a BINAP, a        CatAsium, a TangPhos, a JafaPhos, a DuPhos, a BPE, a Ferrotane,        a BINAM, a DuanPhos, a Nor Phos, a BDPP, a ProPhos, a DIPAMP, a        ChiraPhos ligand or a Binaphane ligand. For example, the        transition metal catalyst comprises the transition metal rhodium        and a chiral ligand such as SL-P104-2, SL-P102-1, SL-P005-1,        (R)—P-Phos, (S)—P-Phos, (S)-PhanePhos, (R)-PhanePhos,        (R)-An-PhanePhos, (R)-MeO-Xyl-PhanePhos, (R)-Xyl-PhanePhos,        (R)-Tol-PhanePhos, (S)-MeBoPhoz, (S,S)-DIOP, (R,R)-DIOP,        (S)-BINAP, (S)-Tol-BINAP, (R)-CatASium M, (S)-CatASium M,        (R)-CatASium MN, (S)-CatASium MN, (R)-CatASium D, (R)-CatASium        MNN, (S,S,R,R)-TangPhos, (R)-JafaPhos, (R)-MeDuPhos,        (S,S)-Me-BPE, (S,S)-Ph-BPE, (S,S)-Et-Ferrotane, (S)-BINAM-P,        (R)-BINAM-P, (R,R)-DuanPhos, (R,R)-NorPhos, (S,S)-NorPhos,        (R,R)-BDPP, (S,S)-BDPP, (R)-ProPhos, (R,R)-DIPAMP,        (S,S)-ChiraPhos or (R)-Binaphane. Particularly suitable        transition metal catalyst are for example: [Rh(COD)(SL-P104-2)]        O₃SCF₃, [Rh(COD)(SL-P102-1)]BF₄, [Rh(COD)(SL-P005-1)]BF₄,        [Rh(COD)(SL-P102-1)] O₃SCF₃, [(R)—P-Phos Rh(COD)]BF₄,        [(S)—P-Phos Rh(COD)]BF₄, [(R)-PhanePhos Rh(COD)]BF₄,        [(S)-PhanePhos Rh(COD)]BF₄, [(R)-Xyl-PhanePhos Rh(COD)]BF₄,        [(S)-MeBoPhoz Rh(COD)]BF₄, [(S,S)-DIOP Rh(COD)]BF₄, [(S)-BINAP        Rh(COD)]BF₄, [(R)-CatASium M Rh(COD)]BF₄, [(S)-CatASium M        Rh(COD)]BF₄, [(R)-CatASium MN Rh(COD)]BF₄, [(S)-CatASium MN        Rh(COD)]BF₄, [(R)-CatASium D Rh(COD)]BF₄, [(S,S,R,R)-TangPhos        Rh(COD)]BF₄, [(R)-JafaPhos Rh(COD)]BF₄, [(R)-MeDuPhos        Rh(COD)]BF₄, [(S,S)-Me-BPE Rh(COD)]BF₄, [(S,S)-Ph-BPE        Rh(COD)]BF₄, [(S,S)-Et-Ferrotane Rh(COD)]BF₄, [(R)-An-PhanePhos        Rh(COD)]BF₄, [(R)-CatASium MNN Rh(COD)]BF₄, [(S)-Tol-BINAP        Rh(COD)]BF₄, [(S)-BINAM-P Rh(COD)]BF₄, [(R)-BINAM-P Rh(COD)]BF₄,        [(R,R)-DuanPhos Rh(COD)]BF₄, [(R)-Binaphane Rh(COD)]BF₄,        [(R,R)-NorPhos Rh(COD)]BF₄, [(S,S)-NorPhos Rh(COD)]BF₄,        [(R,R)-BDPP Rh(COD)]BF₄, [(S,S)-BDPP Rh(COD)]BF₄, [(R,R)-DIOP        Rh(COD)]BF₄, [(R)-ProPhos Rh(COD)]BF₄, [(R,R)-DIPAMP        Rh(COD)]BF₄, [(S,S)-ChiraPhos Rh(COD)]BF₄,        [(R)-MeO-Xyl-PhanePhos Rh(COD)]BF₄ or [(R)-Tol-PhanePhos        Rh(COD)]BF₄; in particular [Rh(COD)(SL-P102-1)]BF₄,        [Rh(COD)(SL-P005-1)]BF₄, [Rh(COD)(SL-P102-1)] O₃SCF₃,        [(R)-PhanePhos Rh(COD)]BF₄, [(R)Xyl-PhanePhos Rh(COD)]BF₄,        [(S,S)-DIOP Rh(COD)]BF₄, [(S)-BINAP Rh(COD)]BF₄, [(R)-CatASium M        Rh(COD)]BF₄, [(R)-CatASium MN Rh(COD)]BF₄, [(S)-CatASium MN        Rh(COD)]BF₄, [(S,S,R,R)-TangPhos Rh(COD)]BF₄, [(S,S)-Me-BPE        Rh(COD)]BF₄, [(S,S)-Ph-BPE Rh(COD)]BF₄, [(R)-An-PhanePhos        Rh(COD)]BF₄, [(R)-CatASium MNN Rh(COD)]BF₄, [(S)Tol-BINAP        Rh(COD)]BF₄, [(S)-BINAM-P Rh(COD)]BF₄, [(R,R)-DuanPhos        Rh(COD)]BF₄, [(R)-Binaphane Rh(COD)]BF₄, [(S,S)-NorPhos        Rh(COD)]BF₄, [(R,R)-BDPP Rh(COD)]BF₄, [(S,S)-BDPP Rh(COD)]BF₄,        [(R,R)-DIOP Rh(COD)]BF₄, [(R)-ProPhos Rh(COD)]BF₄, [(R,R)-DIPAMP        Rh(COD)]BF₄, [(S,S)-ChiraPhos Rh(COD)]BF₄,        [(R)-MeO-Xyl-PhanePhos Rh(COD)]BF₄ or [(R)-Tol-PhanePhos        Rh(COD)]BF₄; such as [Rh(COD)(SL-P102-1)]BF₄,        [Rh(COD)(SL-P005-1)]BF₄, [(R)PhanePhos Rh(COD)]BF₄,        [(R)Xyl-PhanePhos Rh(COD)]BF₄, [(R)CatASium M Rh(COD)]BF₄,        [(R)CatASium MN Rh(COD)]BF₄, [(S,S,R,R)TangPhos Rh(COD)]BF₄,        [(S,S)Ph-BPE Rh(COD)]BF₄, [(R)An-PhanePhos Rh(COD)]BF₄,        [(R,R)DuanPhos Rh(COD)]BF₄, [(S,S)Nor Phos Rh(COD)]BF₄ or        [(R)MeO-Xyl-PhanePhos Rh(COD)]BF₄;    -   the transition metal ruthenium and a chiral ligand such as a        BoPhoz, a BINAP, a BINOL, a PhanePhos, a P-Phos or a QUINAPHOS        ligand. For example, the transition metal catalyst comprises the        transition metal ruthenium and a chiral ligand such as        (R)-4-F—C₆H₄-MeBoPhoz, (R)-BINAP, (R)-BINOL-(R)-MeBoPhoz,        (R)-MeBoPhoz, (R)-p-F-MeBoPhoz, (R)-PhanePhos,        (R)-Phenethyl-(R)-MeBoPhoz, (R)—P-Phos, (R)-Tol-BINAP,        (R)-Xyl-PhanePhos, (R)-Xyl-P-Phos, (R_(a),S_(c))1Np-QUINAPHOS,        (S)-BINAP, (S)-BINOL-(R)-MeBoPhoz, (S)—P-Phos,        (S)-Xyl-PhanePhos, (S)-Xyl-P-Phos or (Sa,Rc)1Np-QUINAPHOS.        Particularly suitable transition metal catalyst are for example:        [(R)-4-F—C₆H₄-MeBoPhoz Ru(benzene)Cl]Cl, [(R)-BINAP        RuCl(benzene)]Cl, [(R)-BINOL-(R)-MeBoPhoz Ru(benzene)Cl]Cl,        [(R)-MeBoPhoz RuCl(Benzene)]Cl, [(R)-p-F-MeBoPhoz        RuCl(Benzene)]Cl, [(R)-PhanePhos RuCl₂(dmf)₂],        [(R)-Phenethyl-(R)-MeBoPhoz Ru(benzene)Cl]Cl, [(R)—P-Phos        RuCl(benzene)]Cl, [(R)-Tol-BINAP RuCl(benzene)]Cl,        [(R)-Xyl-PhanePhos RuCl₂(dmf)₂], [(R)-Xyl-P-Phos RuCl₂(dmf)₂],        [(R_(a),S_(c))1Np-QUINAPHOS RuCl₂(dmf)₂], [(S)-BINAP        RuCl(benzene)]Cl, [(S)-BINOL-(R)-MeBoPhoz Ru(benzene)Cl]Cl,        [(S)—P-Phos RuCl(benzene)]Cl, [(S)-Xyl-PhanePhos RuCl₂(dmf)₂],        [(S)-Xyl-P-Phos RuCl₂(dmf)₂], [(S_(a),R_(c))1Np-QUINAPHOS        RuCl₂(dmf)₂], [(R)—P-Phos Ru(acac)₂], [(R)-Xyl-P-Phos Ru(acac)₂]        or [(R)-Xyl-P-Phos RuCl(benzene)]Cl; in particular,        [(R)-4-F—C₆H₄-MeBoPhoz Ru(benzene)Cl]Cl, [(R)-BINAP        RuCl(benzene)]Cl, [(R)-MeBoPhoz RuCl(Benzene)]Cl,        [(R)-p-F-MeBoPhoz RuCl(Benzene)]Cl, [(R)-PhanePhos RuCl₂(dmf)₂],        [(R)-Phenethyl-(R)-MeBoPhoz Ru(benzene)Cl]Cl, [(R)—P-Phos        RuCl(benzene)]Cl, [(R)-Tol-BINAP RuCl(benzene)]Cl,        [(R)-Xyl-P-Phos RuCl₂(dmf)₂], [(S)-BINAP RuCl(benzene)]Cl,        [(S)-BINOL-(R)-MeBoPhoz Ru(benzene)Cl]Cl, [(S)—P-Phos        RuCl(benzene)]Cl, [(S)-Xyl-PhanePhos RuCl₂(dmf)₂],        [(Sa,Rc)1Np-QUINAPHOS RuCl₂(dmf)₂], [(R)—P-Phos Ru(acac)₂],        [(R)-Xyl-P-Phos Ru(acac)₂] or [(R)-Xyl-P-Phos RuCl(benzene)]Cl;        or    -   the transition metal iridium and a chiral ligand such as a        P-Phos, a BoPhoz, a SimplePHOX or a PHOX ligand. For example,        the transition metal catalyst comprises the transition metal        iridium and a chiral ligand such as (S)—P-Phos, (S)-Xyl-P-Phos,        (S)-MeBoPhoz, (R)-MeBoPhoz, (S)-Cy-tBu-SimplePHOX or        (S)-iPr-PHOX. Particularly suitable transition metal catalyst        are for example: [(S)—P-Phos Ir(COD)]Cl, [(S)-Xyl-P-Phos        Ir(COD)]Cl, [(S)-MeBoPhoz Ir(COD)]Cl, [(R)-MeBoPhoz Ir(COD)]Cl,        [(S)-Cy-tBu-simplePHOX Ir(COD)]BArF or [(S)-iPr-PHOX        Ir(COD)]BArF.

When using these combinations, the reduction of the compound of formula(2-a), or salt thereof, provides a composition comprising the compoundsaccording to formulae (1-a) and (1-b), or salts thereof, wherein themolar ratio of compounds according to formula (1-a), or salts thereof,to compounds according to formula (1-b), or salts thereof, is at least55 to 45, preferably at least 80 to 20, more preferably at least 97 to3, most preferably at least 99 to 1.

In a fourth embodiment, the reduction of the compound of formula (2-a),or salt thereof, provides a composition comprising the compoundsaccording to formulae (1-a) and (1-b), or salts thereof, wherein themolar ratio of compounds according to formula (1-b), or salts thereof,to compounds according to formula (1-a), or salts thereof, is at least55 to 45, preferably at least 70 to 30, more preferably at least 76 to24.

In one embodiment, the transition metal catalyst comprises, for example:

-   -   the transition metal rhodium and a chiral ligand such as a        PhanePhos, a BoPhoz, a JafaPhos, a CatASium, a BINAM or a Nor        Phos ligand. For example, the transition metal catalyst        comprises the transition metal rhodium and a chiral ligand such        as (S)-PhanePhos, (S)-MeBoPhoz, (R)-JafaPhos, (S)-CatASium M,        (R)-BINAM-P or (R,R)-Norphos. Particularly suitable transition        metal catalyst are for example: [(S)-PhanePhos Rh(COD)]BF₄,        [(S)-MeBoPhoz Rh(COD)]BF₄, [(R)-JafaPhos Rh(COD)]BF₄,        [(S)-CatASium M Rh(COD)]BF₄, [(R)-BINAM-P Rh(COD)]BF₄ or        [(R,R)-NorPhos Rh(COD)]BF₄;    -   the transition metal ruthenium and a chiral ligand such as a        PhanePhos, a P-Phos, a BINOL, a QUINAPHOS, a BoPhoz or a BINAP        ligand. For example, the transition metal catalyst comprises the        transition metal ruthenium and a chiral ligand such as        (S)-Xyl-PhanePhos, (S)-Xyl-P-Phos, (R)-BINOL-(R)-MeBoPhoz,        (R_(a),S_(c))1Np-QUINAPHOS or (R)-Tol-BINAP. Particularly        suitable transition metal catalyst are for example        [(S)Xyl-PhanePhos RuCl₂(dmf)₂], [(S)Xyl-P-Phos RuCl₂(dmf)₂],        [(R)BINOL-(R)-MeBoPhoz Ru(benzene)Cl]Cl,        [(R_(a),S_(c))1Np-QUINAPHOS RuCl₂(dmf)₂] or [(R)Tol-BINAP        RuCl(benzene)]Cl; or    -   the transition metal iridium and a chiral ligand such as a        P-Phos or BoPhoz ligand, for example (S)-Xyl-P-Phos or        (S)-MeBoPhoz. Particularly suitable transition metal catalyst        are for example [(S)-Xyl-P-Phos Ir(COD)]Cl or [(S)-MeBoPhoz        Ir(COD)]Cl.

When using these combinations, the reduction of the compound of formula(2-a), or salt thereof, provides a composition comprising the compoundsaccording to formulae (1-a) and (1-b), or salts thereof, wherein themolar ratio of compounds according to formula (1-b), or salts thereof,to compounds according to formula (1-a), or salts thereof, is at least55 to 45, preferably at least 70 to 30, more preferably at least 76 to24.

In a further preferred embodiment, the reduction of the compound offormula (2-a), or salt thereof, provides a composition comprising thecompounds according to formulae (1-a) and (1-b), or salts thereof,wherein the molar ratio of compounds according to formula (1-a), orsalts thereof, to compounds according to formula (1-b), or saltsthereof, is at least 88 to 12, preferably at least 90 to 10, morepreferably at least 99 to 1.

SECTION D: CONVERSION OF A COMPOUND OF FORMULA (7) INTO A COMPOUND OFFORMULA (1) VIA A COMPOUND OF FORMULA (3)

The methods, according to the present invention, to convert a compoundformula (7), as described herein, into a compound of formula (3), asdescribed herein, are summarized in Scheme 5.

Thus, in another aspect the present invention relates to the conversionof a compound of formula (7), as described herein, into a compound offormula (3), as described herein, according to any one of methods 1 to5, wherein

method 1 comprises

-   -   a) any one of methods in Section B to convert (7) into (5), and    -   b) any one of methods in Section D.1 to convert (5) into (3);        method 2 comprises any one of methods in Section D.2 to        convert (7) into (3);        method 3 comprises    -   a) any one of methods in Section B to convert (7) into (6),    -   b) any one of methods in Section B to convert (6) into (5), and    -   c) any one of methods in Section D.1 to convert (5) into (3);        method 4 comprises    -   a) any one of methods in Section B to convert (7) into (6), and    -   b) any one of methods in Section D.3 to convert (6) into (3);        method 5 comprises    -   a) any one of methods in Section B to convert (7) into (6),    -   b) any one of methods in Section B to convert (6) into (4), and    -   c) any one of methods in Section D.4 to convert (4) into (3);        in particular according to methods 1, 2, 4 or 5; particularly        according to method 5.

As discussed below, Sections D.1, D.2, D.3 and D.4 as such are alsopreferred embodiments of the present invention.

Section D.1: Conversion of a Compound of Formula (5) into a Compound ofFormula (3)

In a further aspect, the present invention relates to a process forpreparing a compound of formula (3)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, said processcomprisinga) converting a compound of formula (5), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, into a compoundof formula (12)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R5 is a leaving group; andb) reacting the compound of formula (12), or salt thereof, with areducing agent to obtain the compound of formula (3).

Steps a) and b) as such are also an embodiment of the present invention.

In a preferred embodiment, the present invention relates to a processfor preparing a compound of formula (3-a)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, said processcomprisinga) converting a compound of formula (5-b), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group,into a compound of formula (12-b)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R5 is a leaving group; andb) reacting the compound of formula (12-b), or salt thereof, with areducing agent to obtain the compound of formula (3).

Typical reducing agents are well known in the art and can be taken e.g.from relevant chapters of standard reference works such as P. G. M. Wutsand T. W. Greene, “Greene's Protective Groups in Organic Synthesis’,Fourth Edition, Wiley, New Jersey, 2007 and include:

-   -   hydrides (eg lithium aluminium hydride, sodium borohydride,        sodium cyanoborohydride), metals (eg zinc, tin dichloride,        tributyltin hydride, lithium), hydrogenation (eg hydrogen and a        hydrogenation catalyst such as Pd/C, for example as described in        Section B.3.3) [especially when R5=halide],    -   hydrides (eg lithium aluminium hydride, sodium borohydride,        diisobutyl aluminium hydride) or tributyltin hydride-sodium        iodide. [especially when R5=sulphonate]

In general, these methods work for both halides and suphonates

Steps a) and b) as such are also a preferred embodiment of the presentinvention.

The conversion of a OH-group into a leaving group and the subsequenttreatment with a reducing agent are well-known reactions to the personskilled in the art, for example as described in Richard C. Larock,“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations”, Second Edition, Wiley-VCH Verlag GmbH, 2000, inparticular as described in the relevant chapters thereof. Preferredleaving groups are halo, such as bromo or iodo, or a sulphonate group,such as tosylate, mesylate or triflate. Preferred reducing agents are,for example, hydrides (LiAlH₄, NaBH₄) and hydrogen in the presence of ahydrogenation catalysts (eg Pd/C) [see Section B.3.3 above].

Section D.2: Conversion of a Compound of Formula (7) into a Compound ofFormula (3)

In a further aspect, the present invention relates to a process forpreparing a compound of formula (3)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, said processcomprising treating a compound of formula (7),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand, R6 and R7 are, independently, an alkyl group, an aryl group, anarylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle,together with the nitrogen to which they are attached, which cycle maybe saturated or unsaturated and may optionally contain one or moreheteroatoms, such a nitrogen, oxygen or sulphur, whereby the cyclecontains 3 to 8, such as 4 to 7 ring atoms,with a reducing agent to obtain the compound of formula (3), or saltthereof, wherein R1 is hydrogen or a nitrogen protecting group,preferably of formulae (3-a) or (3-b), more preferably of formula (3-a),

In a preferred embodiment, the starting compound of formula (7), or saltthereof, is according to formula (7-a), or salt thereof, as definedabove; more preferably the starting compound is according to formulae(7b) or (7c), or salts thereof, as defined above.

Preferred reducing agents are, for example, hydrogen in the presence ofa heterogeneous hydrogenation catalysts, for example, palladium orplatinum on a solid support, for example, on carbon, alumina, bariumcarbonate or calcium carbonate, in particular on carbon, alumina orbarium carbonate. Preferably, palladium on carbon (Pd/C) or palladium oncalcium carbonate (Pd/CaCO₃) which is poisoned with lead (known in theart as Lindlar catalyst) is used, in particular palladium on carbon(Pd/C).

In a preferred embodiment, the reduction of the compound of formula(7-a), or salt thereof, provides a composition comprising the compoundsaccording to formulae (3-a) and (3-b), or salts thereof, wherein themolar ratio of compounds according to formula (3-a), or salts thereof,to compounds according to formula (3-b), or salts thereof, is at least88 to 12, preferably at least 90 to 10, more preferably at least 99 to1.

Section D.3: Conversion of a Compound of Formula (6) into a Compound ofFormula (3)

In a further aspect, the present invention relates to a process forpreparing a compound of formula (3)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, said processcomprising treating a compound of formula (6),

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,with a reducing agent, for example as described in Section B.3.3, toobtain the compound of formula (3), or salt thereof, wherein R1 ishydrogen or a nitrogen protecting group, preferably of formulae (3-a) or(3-b), as defined herein, more preferably of formula (3-a), as definedherein.

In a preferred embodiment, the starting compound of formula (6), or saltthereof, is according to formula (6-a), or salt thereof, as definedherein.

In a preferred embodiment, the reduction of the compound of formula(6-a), or salt thereof, provides a composition comprising the compoundsaccording to formulae (3-a) and (3-b), or salts thereof, wherein themolar ratio of compounds according to formula (3-a), or salts thereof,to compounds according to formula (3-b), or salts thereof, is at least88 to 12, preferably at least 90 to 10, more preferably at least 99 to1.

Section D.4: Reduction of a Compound of Formula (4)

In a further aspect, the present invention relates to a process forpreparing a compound according to formula (3),

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, comprisingreducing a compound according to formula (4),

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, to obtain thecompound of formula (3).

Preferably, a compound according to formula (4-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, is used asstarting compound. If the compound (4-a), or salt thereof, is used asstarting compound, compounds according to formula (3-a) and formula(3-b), as defined herein, can be obtained.

Preferably R1 is BOC.

In a preferred embodiment, the reduction of the compound of formula (4),or salt thereof, takes place with hydrogen in the presence of atransition metal catalyst, preferably in the presence of a transitionmetal catalyst and a chiral ligand. The reduction may occur underhetereo- or homogeneous hydrogenation conditions, preferably underhomogeneous hydrogenation conditions.

In one embodiment, the reduction of the compound of formula (4), or saltthereof, takes place under hetereogeneous hydrogenation conditions.

Generally, the hetereogeneous hydrogenation is carried out in thepresence of a transition metal catalyst, wherein the transition metal isselected from group 9 or 10 of the periodic table. Therefore, thetransition metal catalyst comprises, for example, Cobalt (Co), Rhodium(Rh), Iridium (Ir), Nickel (Ni), Palladium (Pd) and/or Platinum (Pt). Inparticular, the transition metal catalyst is Pt, Pd, or Rh, preferablyon a solid support, such as carbon. In one embodiment the transitionmetal catalyst is Pt on carbon (Pt/C) or Pd on carbon (Pd/C).

The heterogeneous hydrogenation of the compound of formula (4), or saltthereof, provides a composition comprising the compounds according toformulae (3-a and (3-b), or salts thereof, wherein the molar ratio ofcompounds according to formula (3-b, or salts thereof, to compoundsaccording to formula (3-a), or salts thereof, is of from at least 67 to33, preferably of from at least 85 to 15.

The hetereogeneous hydrogenation is usually performed in a solvent, suchas ether solvents (eg THF), ester solvents (eg isopropyl acetate) oralcohol solvents (eg isopropanol, ethanol or methanol); in particular analcohol or ester solvent, such ethanol or isopropyl acetate. In oneembodiment, Pd/C is used with ethanol or isopropyl acetate as solvent.In another embodiment, Pt/C is used with isopropyl acetate as solvent.

Generally, the homogeneous hydrogenation is carried out in the presenceof a transition metal catalyst, wherein the transition metal is selectedfrom group 8 or 9 of the periodic table. Therefore, the transition metalcatalyst comprises, for example, the transition metal Iron (Fe),Ruthenium (Ru), Osmium (Os), Cobalt (Co), Rhodium (Rh) and/or Iridium(Ir).

In a preferred embodiment, the transition metal catalyst comprises anorganometallic complex and optionally a chiral ligand.

The organometallic complex comprises a transition metal selected fromgroup 8 or 9 of the periodic table, for example the transition metalrhodium, iridium or ruthenium in particular rhodium or ruthenium. Theorganometallic complexes can comprise a single transition metal atom. Inpreferred embodiments the complexes can comprise two or more transitionmetal atoms, optionally comprising a metal-metal bond. In a preferredembodiment two metal atoms are bridged via two halides. Generally, theorganometallic complex, comprises one or more transition metal atoms andsuitable achiral ligands.

Suitable achiral ligands for the organometallic complex generally areσ-donor ligands, σ-donor/π-acceptor ligands or σ,π-donor/π-acceptorligands. Examples for suitable achiral ligands are among others carbonmonoxide, halides (e.g. Cl, I or Br), phosphines [e.g.tricyclohexylphosphine (PCy₃)], alkenyls (e.g. cod, nbd, 2-metallyl),alkynyls, aryls (e.g. pyridine, benzene, p-cymene), carbonyls (e.g.acac, trifluoroacetate or dimethylformamide) and mixtures thereof.

Examples of preferred achiral ligands for the organometallic complexare: norbornadiene (nbd), cyclooctadiene (cod), pyridine (pyr), cymene,in particular p-cymene, and iodide.

Examples for organometallic complexes are: a ruthenium organometalliccomplex, such as [RuI₂(p-cymene)]₂, [Ru(cod)(2-metallyl)₂] or[Ru(cod)(OOCCF₃)₂]; a rhodium organometallic complex, such as[Rh(nbd)₂BF₄] or [Rh(cod)₂]BF₄; or an iridium organometallic complexsuch as [(Cy₃P)Ir(pyr)]Cl or [Ir(cod)₂Cl]₂; in particular[Ru(cod)(2-metallyl)₂], [Ru(cod)(OOCCF₃)₂] or [RuI₂(p-cymene)]₂; inparticular [Rh(NBD)₂]BF₄, [Ru(COD)(OOCCF₃)₂] or [RuCl₂(p-cymene)₂].

The transition metal catalyst comprises an organometallic complex and achiral ligand. The chiral ligand comprises, for example, a chiralphosphine and/or a chiral ferrocene. In particular, the chiral ferrocenecomprises a Cp-ligand which is substituted with a chiral group, such asa chiral amine, a chiral phosphine or a chiral alkyl, for example asillustrated herein.

Suitable chiral ligands are, for example, an Atropisomer ligand (e.g.SL-A101-2), a Fenphos ligand (e.g. SL-F115-1), a Mandyphos ligand (e.g.SL-M004-2), a Walphos ligand (e.g. SL-WO08-1), a Josiphos ligand (e.gSL-J504-1 or SL-J002-2) or mixtures thereof. Atropisomer ligands,Fenphos ligands, Mandyphos ligands, Walphos ligands and Josiphos ligandsare of the formulae described in Section C.2.

Suitable combinations of organometallic complex and chiral ligand are,for example:

-   -   rhodium organometallic complex and a Fenphos or Walphos ligand;        in particular [Rh(nbd)₂]BF₄ and SL-F115-1 or SL-WO08-1; or    -   ruthenium organometallic complex and an Atropisomer a Mandyphos        or a Josiphos ligand; in particular [RuI₂(p-cymene)]₂ or        [Ru(COD)(OOCCF₃)₂] and SL-A101-2, SL-M004-2, SL-J504-1 or        SL-J002-2.

In one embodiment, the reduction of the compound of formula (4-a), orsalt thereof, provides a composition comprising the compounds accordingto formulae (3-a) and (3-b), or salts thereof, wherein the molar ratioof compounds according to formula (3-a), or salts thereof, to compoundsaccording to formula (3-b), or salts thereof, is at least 88 to 12,preferably at least 90 to 10, more preferably at least 99 to 1.

In another embodiment, the reduction of the compound of formula (4-a),or salt thereof, provides a composition comprising the compoundsaccording to formulae (3-a) and (3-b), or salts thereof, wherein themolar ratio of compounds according to formula (3-a), or salts thereof,to compounds according to formula (3-b), or salts thereof, is at least53 to 47, preferably at least 71 to 29, more preferably at least 82 to18.

Alternative combinations of organometallic complex and chiral ligandare, for example:

-   -   rhodium organometallic complex and a Fenphos or Walphos ligand;        in particular [Rh(nbd)₂]BF₄ and SL-WO08-1.

In another embodiment, the reduction of the compound of formula (4-a),or salt thereof, provides a composition comprising the compoundsaccording to formulae (3-a) and (3-b), or salts thereof, wherein themolar ratio of compounds according to formula (3-b), or salts thereof,to compounds according to formula (3-a), or salts thereof, is at least73 to 27.

SECTION E

In the processes shown above several novel and inventive compounds areinvolved. Consequently, further subjects of the present invention arethe compounds shown below.

A compound according to formula (2),

or salt thereof,wherein R1 and R2 are, independently of each other, hydrogen or anitrogen protecting group, and R3 is a carboxyl group or an ester group,preferably having a configuration according to formula (2-a),

In a preferred embodiment of formulae (2) or (2-a), R1 is BOC and/or R2is H.

In a preferred embodiment of formulae (2) or (2-a), R3 is CO₂H.

A compound of formula (4)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, preferably havinga configuration according to formula (4-a),

In a preferred embodiment of formulae (4) or (4-a), R1 is BOC or Piv.

A compound of formula (5), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, preferably offormulae (5-a), (5-b) or (5-c), more preferably (5-b),

In a preferred embodiment of formulae (5), (5-a), (5-b) or (5-c), R1 isBOC.

A compound of formula (6), or a tautomer thereof,

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, preferably havinga configuration according to formula (6-a),

In a preferred embodiment of formulae (6) or (6-a), R1 is BOC or Piv.

A compound of formula (7), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, preferably having a configuration according toformula (7-a), (7-b) or (7-c), more preferably (7-b),

In a preferred embodiment of formulae (7), (7-a) or (7-b), R1 is BOC orPiv.

In a preferred embodiment of formulae (7), (7-a) or (7-b), R6 is Methylor Ethyl and/or R7 is Methyl or Ethyl.

A compound of formula (9-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group or together are an alkylene group,preferably having a configuration according to formula (9-a) (9-b) or(9-c), more preferably (9-b),

In a preferred embodiment of formulae (9), (9-a), (9-b) or (9-c), R1 isBoc.

In a preferred embodiment of formulae (9), (9-a), (9-b) or (9-c), R6 isMethyl and R7 is Methyl.

A compound of formula (10), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, R6 and R7 are,independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, Z⁻ is a halide (eg iodide, bromide, chloride), analkyl sulphate (eg methyl sulphate) or a sulfonyl ester (eg triflate)and R10 is hydrogen, alkyl or aryl; preferably having a configurationaccording to formula (10-a), (10-b) or (10-c), more preferably (10-b),

In a preferred embodiment of formulae (10), (10-a), (10-b) or (10-c), R1is Boc.

In a preferred embodiment of formulae (10), (10-a), (10-b) or (10-c), R6is Methyl, R7 is Methyl and/or R10 is Methyl.

A compound of formula (11)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R4 is an OH-activating group, preferably having a configurationaccording to formula (11-a), (11-b) or (11-c), more preferably (11-b),

In a preferred embodiment of formulae (11), (11-a), (11-b) or (11-c), R1is Boc.

In a preferred embodiment of formulae (11), (11-a), (11-b) or (11-c), R4is mesylate.

A compound of formula (12)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R5 is a leaving group; preferably of formulae (12-a), (12-b) or(12-c), more preferably (12-b),

In a preferred embodiment of formulae (12), (12-a), (12-b) or (12-c), R1is Boc.

In a preferred embodiment of formulae (12), (12-a), (12-b) or (12-c), R5is a halide, preferably bromide or iodide.

A compound of formula (16)

or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, Y is O or S andeach R9, is, independently, alkyl, aryl, arylalkyl or acetyl.preferably having a configuration according to formula (16-a),

In a preferred embodiment of formulae (16) or (16-a), R1 is Boc.

In a preferred embodiment of formulae (16) or (16-a), R9 is methyl orethyl.

In a preferred embodiment of formulae (16) or (16-a), Y is oxygen.

GENERAL TERMS

The general definitions used above and below, unless defineddifferently, have the following meanings:

The term “ester group” comprises any ester of a carboxyl group generallyknown in the art; for example groups —COOR, wherein R is selected fromthe group consisting of: C₁₋₆alkyl, such as methyl, ethyl or t-butyl,C₁₋₆alkoxyC₁₋₆alkyl, heterocyclyl, such as tetrahydrofuranyl,C₆₋₁₀aryloxyC₁₋₆alkyl, such as benzyloxymethyl (BOM), silyl, such astrimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, cinnamyl,allyl, C₁₋₆alkyl which is mono-, di- or trisubstituted by halogen,silyl, cyano or C₁₋₆aryl, wherein the aryl ring is unsubstituted orsubstituted by one, two or three, residues selected from the groupconsisting of C₁₋₇alkyl, C₁₋₇alkoxy, halogen, nitro, cyano and CF₃; orC₁₋₂alkyl substituted by 9-fluorenyl. In a preferred embodiment, the“ester group” is —COOR, wherein R is a C₁₋₆alkyl residue. In particular,R is methyl or ethyl.

The term “nitrogen protecting group” comprises any group which iscapable of reversibly protecting a nitrogen functionality, preferably anamine and/or amide functionality. Preferably the nitrogen protectinggroup is an amine protecting group and/or an amide protecting group.Suitable nitrogen protecting groups are conventionally used in peptidechemistry and are described e.g. in the relevant chapters of standardreference works such as J. F. W. McOmie, “Protective Groups in OrganicChemistry”, Plenum Press, London and New York 1973, in P. G. M. Wuts andT. W. Greene, “Greene's Protective Groups in Organic Synthesis’, FourthEdition, Wiley, New Jersey, 2007, in “The Peptides”; Volume 3 (editors:E. Gross and J. Meienhofer), Academic Press, London and New York 1981,and in “Methoden der organischen Chemie” (Methods of Organic Chemistry),Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart1974.

Preferred nitrogen protecting groups generally comprise:

C₁-C₆-alkyl, preferably C₁-C₄-alkyl, more preferably C₁-C₂-alkyl, mostpreferably C₁-alkyl which is mono-, di- or tri-substituted bytrialkylsilylC₁-C₇alkoxy (eg. trimethylsilyethoxy) aryl, preferablyphenyl, or an heterocyclic group, preferably pyrrolidinyl, wherein thearyl ring or the heterocyclic group is unsubstituted or substituted byone or more, e.g. two or three, residues, e.g. selected from the groupconsisting of C₁-C₇alkyl, hydroxy, C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy,halogen, nitro, cyano, and CF₃; aryl-C1-C2-alkoxycarbonyl (preferablyphenyl-C1-C2-alkoxycarbonyl eg. benzyloxycarbonyl);C₁₋₁₀alkenyloxycarbonyl; C₁₋₆alkylcarbonyl (eg. acetyl or pivaloyl);C₆₋₁₀arylcarbonyl; C₁₋₆alkoxycarbonyl (eg. t-butoxycarbonyl);C₆₋₁₀arylC₁₋₆alkoxycarbonyl; allyl or cinnamyl; sulfonyl or sulfenyl;succinimidyl group, silyl, e.g. triarylsilyl or trialkylsilyl (eg.triethylsilyl).

Examples of preferred nitrogen protecting groups are acetyl, benzyl,cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz),9-fluorenylmethyloxycarbony (Fmoc), benzyloxymethyl (BOM),pivaloyl-oxy-methyl (POM), trichloroethxoycarbonyl (Troc),1-adamantyloxycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl,tert.-butyl-dimethylsilyl, triethylsilyl (TES), triisopropylsilyl,trimethylsilyethoxymethyl (SEM), t-butoxycarbonyl (BOC), t-butyl,1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene, pyrridinyl andpivaloyl. Most preferred nitrogen protecting groups are acetyl, benzyl,benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilyethoxymethyl(SEM), t-butoxycarbonyl (BOC), pyrrolidinylmethyl and pivaloyl.

Examples of more preferred nitrogen protecting groups are pivaloyl,pyrrolidinylmethyl, t-butoxycarbonyl, benzyl and silyl groups,particularly silyl groups according to the formula SiR11R12R13, whereinR11, R12 and R13 are, independently of each other, alkyl or aryl.Preferred examples for R11, R12 and R13 are methyl, ethyl, isopropyl,t-butyl and phenyl.

Particularly preferred as nitrogen protecting groups are pivaloyl andt-butoxycarbonyl (BOC).

Alkyl is defined as a radical or part of a radical is a straight orbranch (one or, if desired and possible, more times) carbon chain, andis especially C₁-C₇alkyl, preferably C₁-C₄-alkyl.

The term “C₁-C₇-” defines a moiety with up to and including maximally 7,especially up to and including maximally 4, carbon atoms, said moietybeing branched (one or more times) or straight-chained and bound via aterminal or a non-terminal carbon

Cycloalkyl is, for example, C₃-C₇-cycloalkyl and is, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.Cyclopentyl and cyclohexyl are preferred.

Alkoxy is, for example, C₁-C₇alkoxy and is, for example, methoxy,ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy,sec-butyloxy, tert-butyloxy and also includes corresponding pentyloxy,hexyloxy and heptyloxy radicals. C₁-C₄alkoxy is preferred.

Alkanoyl is, for example, C₂-C₈-alkanoyl and is, for example, acetyl[—C(═O)Me], propionyl, butyryl, isobutyryl or pivaloyl. C₂-C₅-Alkanoylis preferred, especially acetyl.

Halo or halogen is preferably fluoro, chloro, bromo or iodo, mostpreferably, chloro, bromo, or iodo.

Halo-alkyl is, for example, halo-C₁-C₇alkyl and is in particularhalo-C₁-C₄alkyl, such as trifluoromethyl, 1,1,2-trifluoro-2-chloroethylor chloromethyl. Preferred halo-C₁-C₇alkyl is trifluoromethyl.

Alkenyl may be linear or branched alkyl containing a double bond andcomprising preferably 2 to 12 C atoms, 2 to 10 C atoms being especiallypreferred. Particularly preferred is a linear C₂₋₄alkenyl. Some examplesof alkyl groups are ethyl and the isomers of propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl,hexadecyl, octacyl and eicosyl, each of which containing a double bond.Especially preferred is allyl.

Alkylene is a bivalent radical derived from C₁₋₇alkyl and is especiallyC₂-C₇alkylene or C₂-C₇-alkylene and, optionally, can be interrupted byone or more, e.g. up to three, O, NR14 or S, wherein R14 is alkyl, eachof which can be unsubstituted or substituted, by one or moresubstituents independently selected from for example, C₁-C₇alkyl,C₁-C₇alkoxy-C₁-C₇alkyl or C₁-C₇alkoxy.

Alkenylene is a bivalent radical derived from C₂₋₇alkenyl and can beinterrupted by, one or more, e.g. up to three, O, NR14 or S, wherein R14is alkyl, and is unsubstituted or substituted by one or more, e.g. up tothree, substitutents preferably independently selected from thesubstitutents mentioned above for alkylene.

Aryl being a radical or part of a radical is, for example C₆₋₁₀aryl, andis, preferably a mono- or polycyclic, especially monocyclic, bicyclic ortricyclic aryl moiety with 6 to 10 carbon atoms, preferably phenyl, andwhich can be unsubstituted or substituted, by one or more substituentsindependently selected from for example, C₁-C₇alkyl,C₁-C₇-alkoxy-C₁-C₇-alkyl or C₁-C₇-alkoxy.

The term arylalkyl refers to aryl-C₁-C₇-alkyl, wherein aryl is asdefined herein and is for example benzyl.

The term carboxyl refers to —CO₂H.

Aryloxy refers to a Aryl-O— wherein aryl is as defined above.

Unsubstituted or substituted heterocyclyl is a mono- or polycyclic,preferably a mono-, bi- or tricyclic-, most preferably mono-,unsaturated, partially saturated, saturated or aromatic ring system withpreferably 3 to 14 (more preferably 5 to 14) ring atoms and with one ormore, preferably one to four, heteroatoms independently selected fromnitrogen, oxygen, sulfur, S(═O)— or S-(═O)₂, and is unsubstituted orsubstituted by one or more, e.g. up to three, substitutents preferablyindependently selected from the Preferred substituents are selected fromthe group consisting of halo, C₁-C₇alkyl, C₁-C₇alkoxy,halo-C₁-C₇-alkoxy, such as trifluoromethoxy and C₁-C₇alkoxy-C₁-C₇alkoxy.When the heterocyclyl is an aromatic ring system, it is also referred toas heteroaryl.

Acetyl is —C(═O)C₁-C₇alkyl, preferably —C(═O)Me.

Silyl is —SiRR′R″, wherein R, R′ and R″ are independently of each otherC₁₋₇alkyl, aryl or phenyl-C₁₋₄alkyl.

Sulfonyl is (unsubstituted or substituted) C₁-C₇-alkylsulfonyl, such asmethylsulfonyl, (unsubstituted or substituted) phenyl- ornaphthyl-C₁-C₇-alkylsulfonyl, such as phenyl-methanesulfonyl, or(unsubstituted or substituted) phenyl- or naphthyl-sulfonyl; wherein ifmore than one substituent is present, e.g. one to three substitutents,the substituents are selected independently from cyano, halo,halo-C₁-C₇alkyl, halo-C₁-C₇-alkyloxy- and C₁-C₇-alkyloxy. Especiallypreferred is C₁-C₇alkylsulfonyl, such as methylsulfonyl, and (phenyl- ornaphthyl)-C₁-C₇-alkylsulfonyl, such as phenylmethanesulfonyl.

Sulfenyl is (unsubstituted or substituted) C₆₋₁₀aryl-C₁-C₇-alkylsulfenylor (unsubstituted or substituted) C₆₋₁₀arylsulfenyl, wherein if morethan one substituent is present, e.g. one to four substitutents, thesubstituents are selected independently from nitro, halo,halo-C₁-C₇alkyl and C₁-C₇alkyloxy.

A “heterogeneous” catalyst as used herein refers to a catalyst supportedon a carrier, typically although not necessarily a substrate comprisedof an inorganic material, for example, a porous material such as carbon,silicon and/or aluminum oxide. In one embodiment, the heterogeneouscatalyst is a hydrogenation catalyst, in particular those described inSection D.4.

A “homogeneous” catalyst as used herein refers to a catalyst that is notsupported on a carrier. In one embodiment, the homogeneous catalyst is ahydrogenation catalyst, in particular those described in Section D.4.

The term “transition metal catalyst” refers to an organometalliccatalyst, an organometallic complex or an organometallic complex and achiral ligand. Transition metal catalysts are in particular thosedescribed in Sections C.1, B 3.3 and D.4.

The term “organometallic complex” refers to complexes derived from atransition metal and one or more (for example up to four) achiral (nonchiral) ligands; for example, ruthenium organometallic complexes, suchas [RuI₂(p-cymene)]₂, [Ru(cod)(2-metallyl)₂] or [Ru(cod)(OOCCF₃)₂];rhodium organometallic complexes, such as [Rh(nbd)₂BF₄] or[Rh(cod)₂]BF₄; or an iridium organometallic complexes, such as[(Cy₃P)Ir(Pyr)]Cl or [Ir(cod)₂Cl]₂.

The term “organometallic catalyst” refers to a catalysts derived from atransition metal and one or more (for example up to four) chiralligands.

The term “ligand” means any compound, achiral or chiral, that can form acomplex with a transition metal. Chiral and achiral ligands are inparticular those described in Section C.1

The term “catalyst” means any substance that affects the rate of achemical reaction by lowering the activation energy for the chemicalreaction.

The term “powder” means a catalyst with a water contain of from 0 to 30mass %.

The term “substrate to catalyst ratio” (S/C) refers to the molar ratioof starting compounds, or salts thereof, to “transition metal catalyst”.

The term “chiral” refers to molecules which have the property ofnon-superimposability on their mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “tautomer” refers in particular to the enol tautomer of thepyrrolidin-2-one moiety of the compounds of the present invention.Additionally, the term “tautomer” also refers in particular to thealdehyde tautomer of compounds of the present invention, e.g. compoundsof the formula (6), where such compounds can exists in either an enol oraldehyde form, or mixtures thereof.

In the formulae of the present application the term “

” on a C-sp³ represents a covalent bond, wherein the stereochemistry ofthe bond is not defined. This means that the term “

” on a C-sp³ comprises an (S) configuration as well as an (R)configuration of the respective chiral centre. Furthermore, mixtures arealso encompassed, e.g., mixtures of enantiomers, such as racemates, areencompassed by the present invention.

In the formulae of the present application the term “

” on a C-sp² represents a covalent bond, wherein the stereochemistry orthe geometry of the bond is not defined. This means that the term “

” on a C-sp² comprises a cis (Z) configuration as well as a trans (E)configuration of the respective double bond. Furthermore, mixtures arealso encompassed, e.g., mixtures of double bond isomers are encompassedby the present invention.

The compounds of the present invention can possess one or moreasymmetric centers. The preferred absolute configurations are asindicated herein specifically.

In the formulae of the present application the term “

” on a C-sp³ indicates the absolute stereochemistry, either (R) or (S).

In the formulae of the present application the term “

” on a C-sp³ indicates the absolute stereochemistry, either (R) or (S).

In the formulae of the present application, the term “

” indicates a Csp³-Csp³ bond or a Csp²-Csp² bond.

Salts are especially pharmaceutically acceptable salts or generallysalts of any of the intermediates mentioned herein, where salts are notexcluded for chemical reasons the skilled person will readilyunderstand. They can be formed where salt forming groups, such as basicor acidic groups, are present that can exist in dissociated form atleast partially, e.g. in a pH range from 4 to 10 in aqueous solutions,or can be isolated especially in solid, especially crystalline, form.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds or any of theintermediates mentioned herein with a basic nitrogen atom (e.g. imino oramino), especially the pharmaceutically acceptable salts. Suitableinorganic acids are, for example, halogen acids, such as hydrochloricacid, sulfuric acid, or phosphoric acid. Suitable organic acids are, forexample, carboxylic, phosphonic, sulfonic or sulfamic acids, for exampleacetic acid, propionic acid, lactic acid, fumaric acid, succinic acid,citric acid, amino acids, such as glutamic acid or aspartic acid, maleicacid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- orethane-sulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid,2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid,N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamicacid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy orsulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts, or ammonium salts withammonia or suitable organic amines, such as tertiary monoamines, forexample triethylamine or tri(2-hydroxyethyl)amine, or heterocyclicbases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.

When a basic group and an acid group are present in the same molecule,any of the intermediates mentioned herein may also form internal salts.

For isolation or purification purposes of any of the intermediatesmentioned herein it is also possible to use pharmaceuticallyunacceptable salts, for example picrates or perchlorates.

In view of the close relationship between the compounds andintermediates in free form and in the form of their salts, includingthose salts that can be used as intermediates, for example in thepurification or identification of the compounds or salts thereof, anyreference to “compounds”, “starting materials” and “intermediates”hereinbefore and hereinafter is to be understood as referring also toone or more salts thereof or a mixture of a corresponding free compound,intermediate or starting material and one or more salts thereof, each ofwhich is intended to include also any solvate or salt of any one or moreof these, as appropriate and expedient and if not explicitly mentionedotherwise. Different crystal forms may be obtainable and then are alsoincluded.

Where the plural form is used for compounds, starting materials,intermediates, salts, pharmaceutical preparations, diseases, disordersand the like, this is intended to mean one (preferred) or more singlecompound(s), salt(s), pharmaceutical preparation(s), disease(s),disorder(s) or the like, where the singular or the indefinite article(“a”, “an”) is used, this is not intended to exclude the plural, butonly preferably means “one”.

Any of the lactams according to the present invention, or salts thereof,wherein R1 is hydrogen can be converted into a corresponding protectedlactam, or salt thereof, wherein R1 is a nitrogen protecting group, asdefined above, according to standard methods of organic chemistry knownin the art, in particular reference is made to conventional nitrogenprotecting group methods described in J. F. W. McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London and New York 1973, inP. G. M. Wuts and T. W. Greene, “Greene's Protective Groups in OrganicSynthesis’, Fourth Edition, Wiley, New Jersey, 2007 and in Richard C.Larock, “Comprehensive Organic Transformations: A Guide to FunctionalGroup Preparations”, Second Edition, Wiley-VCH Verlag GmbH, 2000, inparticular, in the relevant chapters thereof.

Analogously, any of the lactams according to the present invention, orsalt thereof, wherein R1 is a nitrogen protecting group, can beconverted into the corresponding lactam, or salt thereof, wherein R1 isa hydrogen, according to standard methods of organic chemistry known inthe art, in particular reference is made to conventional nitrogenprotecting group methods described in the books mentioned above, inparticular, in the relevant sections.

SECTION F: EXAMPLES

The following Examples serve to illustrate the invention withoutlimiting the scope thereof, while they on the other hand representpreferred embodiments of the reaction steps, intermediates and/or theprocess of the present invention.

ABBREVIATIONS

δ chemical shiftμl microlitreAc acetylacac acetylacetoneAn anisyl (4-methoxyphenyl)BArF tetrakis[3,5-bis(trifluoromethyl)phenyl]boronBINOL 2,2′-dihydroxy-1,1′-dinaphthylBn benzylBoc tert-butoxycarbonylBOC₂O di-tert-butyl carbonateCOD=cod cyclooctadieneCp cyclopentadienylCy cyclohexylDABCO 1,4-diazobicyclo[2.2.2]octanede diastereomeric excessdr diastereomeric ratioDMAP 4-(dimethylamino)pyridine

DMF=dmf N,N-dimethylformamide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneDMSO dimethylsulfoxideee enantiomeric excessES electrosprayESI electrospray ionisationEt ethylEtOAc ethyl acetateEtOH ethanolh hour(s)HNMR proton nuclear magnetic resonanceHPLC high performance liquid chromatographyiPr isopropyliPrOAc isopropyl acetateiPrOH isopropanolIR infra redL litreLC-MS liquid chromatography-mass spectrometryLHMDS lithium bis(trimethylsilyl)amideM molaritym/e mass-to-charge ratioMe methyl

2-MeTHF=Me-THF 2-Methyltetrahydrofuran

MeOH methanolmg milligrammin minute(s)ml millilitremmol(s) millimole(s)mol(s) mole(s)MS mass spectrometrynm nanometreNMR nuclear magnetic resonanceNDB=nbd norbornadieneNp naphthylPd/C palladium on carbonPh phenylPiv pivaloylPiv-Cl pivaloyl chlorideppm parts per millionPt/C platinum on carbonpyr pyridineRh/C rhodium on carbonRT=rt room temperaturetBu tertiary-butylTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyTMG 1,1,3,3-tetramethylguanidineTol toluenet_(R) retention timeXyl xylene

In quoting NMR data, the following abbreviations may be used: s,singlet; d, doublet; t, triplet; q, quartet; quint., quintet; m,multiplet.

Example 1 N,N,N′,N′-Tetramethylformamidinium methylsulfate (18, R6=Me,R7=Me)

A mixture of N,N-dimethylformamide (7.31 g) and dimethylsulfate (12.60g) are heated to 60° C. for 4 h. Then dimethylamine in THF (100 ml, 2 Msolution) and toluene (15 ml) are added and the resulting mixture isstirred at reflux for 1 h. The reaction mixture is cooled to roomtemperature and the phases are separated. The lower layer is washedthree times with anhydrous tert-butyl methyl ether to giveN,N,N′,N′-tetramethylformamidinium methylsulfate (18, R6=Me, R7=Me). ¹HNMR(C₆D₆), 7.95 (1H), 3.70 (3H), 3.32 (6H), 3.29 (6H).

Example 2 N,N,N′,N′-Tetramethylformamidinium para-toluenesulfonate (18,R6=Me, R7=Me)

A mixture of p-toluenesulfonyl chloride (20.0 g) and dimethylformamide(38.3 g) is allowed to stand for 2 h at room temperature. The mixture isthen stirred at 120° C. for 2 h. The mixture is then cooled to roomtemperature and the precipitates are removed by filtration. The motherliquor is diluted with acetone and the mixture cooled to 0° C.Filtration affords N,N,N′,N′-tetramethylformamidiniumpara-toluenesulfonate (18, R6=Me, R7=Me) as white crystals. ¹H NMR(D₂O), 7.65-7.60 (2H), 7.39 (1H), 7.30-7.25 (2H), 3.14 (6H), 3.05 (6H),2.31 (3H).

The X-ray Structure of the obtained crystals is shown in FIG. 1.

Crystal Data [Recorded at 100(2) K]

Empirical formula C₁₂H₂₀N₂O₃S Formula weight 272.36 Crystal systemMonoclinic Space group Cc Cell parameters a = 7.998(2) Å b = 14.331(2) Åc = 11.953(2) Å α = 90° β = 103.615(4)° γ = 90° Volume of unit cell1331.5(4) Å³ Z^(*) 4 Calculated density 1.359 mg m⁻³ ^(*)(number ofasymmetric units in the unit cell)

Example 3 N,N,N′,N′-Tetramethylformamidinium hexafluorophosphate (18,R6=Me, R7=Me)

N,N,N′,N′-tetramethylformamidinium methylsulfate (3 g) is added to water(25 ml) and the resulting mixture is cooled to 0° C. This mixture isthen added to a cooled solution of ammonium hexafluorophosphate (4.6 g)in water (25 ml). The so formed precipitate is then collected byfiltration. The precipitate is washed with cold water (2×10 ml) and thenwith diethyl ether (10 ml). Drying in vacuo givesN,N,N′,N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me) as a white solid. ¹H NMR (DMSO-d6), 7.90 (1H), 3.26 (6H), 3.14(6H).

Example 4 N,N,N′,N′-Tetraethylformadinium methylsulfate (18, R6=Et,R7=Et)

A mixture of N,N-diethylformamide (30 g) and dimethylsulfate (37.5 g)are heated to 50° C. for 4 h. Then a mixture of diethylamine (32.6 g)and toluene (20 ml) are added and the resulting mixture is stirred atreflux for 1 h. The reaction mixture is cooled to room temperature andthe phases are separated. The lower layer is washed ten times withdiethyl ether to give N,N,N′,N′-tetraethylformamidinium methylsulfate(18, R6=Et, R7=Et). 1H NMR (DMSO-d6), 7.26 (1H), 3.51 (8H), 3.42 (3H),1.24 (12H) ppm.

Example 5 N,N,N′N′-Tetraethylformamidinium tetrafluoroborate (18, R6=Et,R7=Et)

N,N,N′,N′-Tetraethylformamidinium methylsulfate (4 g) is added to water(25 ml) and the resulting mixture is cooled to 0° C. This mixture isthen added to a cooled solution of ammonium tetrafluoroborate (3.15 g)in water (25 ml). The mixture is then extracted with dichloromethane.Removal of the dichloromethane gives N,N,N′N′-tetraethylformamidiniumtetrafluoroborate (18, R6=Et, R7=Et) as a white solid. 1H NMR (DMSO-d6),7.80 (1H), 3.70-3.40 (8H), 1.40-1.33 (12H).

The X-ray Structure of the obtained crystals is shown in FIG. 2.

Crystal Data [Recorded at 100(2) K]

Empirical formula C₉H₂₁BF₄N₂ Formula weight 244.09 Crystal systemMonoclinic Space group P21/c Cell parameters a = 9.738(2) Å b = 8.580(2)Å c = 15.519(2) Å α = 90° β = 100.840(6)° γ = 90° Volume of unit cell1273.5(4) Å³ Z^(*) 4 Calculated density 1.273 mg m⁻³ ^(*)(number ofasymmetric units in the unit cell)

Example 6 N,N,N′,N′-Tetraethylformamidinium hexafluorophosphate (18,R6=Et, R7=Et)

N,N,N′,N′-Tetraethylformamidinium methylsulfate (4 g) is added to water(25 ml) and the resulting mixture is cooled to 0° C. This mixture isthen added to a cooled solution of ammonium hexafluorophosphate (4.9 g)in water (25 ml). The formed precipitate is collected by filtration. Theprecipitate is then washed with cold water (2×10 ml) and then withdiethyl ether (10 ml). Drying in vacuo givesN,N,N′,N′-tetraethylformamidinium hexafluorophosphate (18, R6=Et, R7=Et)as a yellow solid. 1H NMR (DMSO-d6), 7.92 (1H), 3.85-3.54 (8H),1.45-1.38 (12H).

Example 7 1-Pyrrolidin-1-ylmethylene-pyrrolidinium methylsulfate (18,R6/R7=Pyrrolidinyl)

A mixture of N-formylpyrrolidine (100 g) and dimethylsulfate (126 g) areheated to 80° C. for 4 h. Then a mixture of pyrrolidine (71 g) andtoluene (100 ml) are added and the resulting mixture is stirred atreflux for 1 h. The reaction mixture is cooled to room temperature andthe phases are separated. The lower layer is concentrated in vacuo andtriturated with diethyl ester. The precipitate is collected byfiltration and recrystallised using ethyl acetate to give1-pyrrolidin-1-ylmethylene-pyrrolidinium methylsulfate (18,R6/R7=Pyrrolidinyl). 1H NMR (DMSO-d6), 8.28 (1H), 3.90-3.85 (4H),3.68-3.62 (4H), 3.38 (3H), 1.99-1.90 (4H), 1.86-1.77 (4H).

Example 8 1-Pyrrolidin-1-ylmethylene-pyrrolidinium hexafluorophosphate(18, R6/R7=Pyrrolidinyl)

1-pyrrolidin-1-ylmethylene-pyrrolidinium methylsulfate (5 g) is added towater (25 ml) and the resulting mixture is cooled to 0° C. This mixtureis then added to a cooled solution of ammonium hexafluorophosphate (6.2g) in water (25 ml). The formed precipitate is collected by filtration.The precipitate is washed with cold water (2×10 ml) and then withdiethyl ether (10 ml). Drying in vacuo gives1-pyrrolidin-1-ylmethylene-pyrrolidinium hexafluorophosphate (18,R6/R7=Pyrrolidinyl) as a white solid. m.p. 229-231° C. ¹H NMR (DMSO-d6),8.25 (1H), 3.91-3.83 (4H), 3.67-3.60 (4H), 1.99-1.90 (4H), 1.86-1.77(4H).

Example 9 N,N,N′,N′-Tetraisopropylformamidinium chloride (18, R6=iPr,R7=iPr)

A mixture of phosphorus oxychloride (10.58 g) and diethyl ether (50 ml)is stirred at 0° C. for 10 min. Diisopropylformamide (8.91 g) in diethylether (20 ml) is then added drop-wise over a period of 10 min. Theresulting mixture is then stirred at room temperature for 30 min. Theformed precipitate is allowed to settle and the supernatant removed.Dichloromethane (60 mL) is then added to the mixture. Diisopropylamine(6.98 g) in dichloromethane (20 ml) is then added drop-wise at 0° C.over 10 min. The mixture is then warmed at room temperature and stirredfor a further 1.5 h. Diethyl ether (30 ml) is added and the resultingprecipitate is removed by filtration. The mother liquor is concentratedin vacuo. Acetone (30 ml) is added and the mixture filtered. The motherliquor is then concentrated in vacuo and subsequently is crystallisedwith diethyl ether (30 ml) to give N,N,N′,N′-tetraisopropylformamidiniumchloride (18, R6=iPr, R7=iPr). 1H NMR (DMSO-d6), 7.49 (1H), 4.15-3.95(4H), 1.33 (12H), 1.31 (12H).

Example 10 N,N,N′,N′-Tetraisopropylformamidinium hexafluorophosphate(18, R6=iPr, R7=iPr)

A mixture of N,N-diisopropyllformamide (10 g) in anhydrousdichloromethane (40 mL) is added to a solution of phosphorus oxychloride(11.8 g) in dichloromethane (100 ml) at −78° C. The resulting mixture isstirred for 30 min at −78° C. The reaction mixture is then warmed toroom temperature and stirred for a further 2 h. The mixture is thencooled to 0° C. To this mixture, a solution of diisopropylamine (10.9ml) and triethylamine (10.7 ml) in dichloromethane (50 ml) is addeddropwise over a period of 30 min. The reaction mixture is then allowedto warm slowly to room temperature and stirred for a further 2 h. Themixture is then concentrated in vacuo. Water (25 ml) is added and theresulting mixture is cooled to 0° C. This mixture is then added to acooled solution of ammonium hexafluorophosphate (14.9 g) in water (25ml). The formed precipitate is collected by filtration. The precipitateis washed with cold water (2×10 ml) and then with diethyl ether (10 ml).The material is dried in vacuo and then recrystallised from acetone togive N,N,N′,N′-tetraisopropylformamidinium hexafluorophosphate (18,R6=iPr, R7=iPr) as a colourless solid. 1H NMR (DMSO-d6), 7.48 (1H),4.15-4.00 (4H), 1.36-1.29 (24H).

Example 11 N,N,N′,N′-Tetraisopropylformamidinium tetrafluoroborate (18,R6=iPr, R7=iPr)

A mixture of N,N-diisopropyllformamide (10 g) in anhydrousdichloromethane (40 ml) is added to a solution of phosphorus oxychloride(11.9 g) in dichloromethane (100 ml) at −78° C. The reaction mixture isthen warmed to room temperature and stirred for 2 h. The mixture is thencooled to 0° C. To this mixture, a solution of diisopropylamine (7.8 g)and triethylamine (10.8 ml) in dichloromethane (50 ml) is added dropwiseover a period of 30 min. The reaction mixture is then allowed to warmslowly to room temperature and stirred for a further 2 h. The reactionmixture is washed with aqueous sodium hydroxide (20 ml, 2 M) andsaturated sodium tetrafluoroborate (13.2 g) and extracted withdichloromethane. The organic layer is dried (MgSO₄) and thenconcentrated in vacuo. The residue is taken up in acetone. Addition of amixture of diethyl ether and pentane (4:1, 20.5 ml) followed byfiltration gives N,N,N′,N′-tetraisopropylformamidinium tetrafluoroborate(18, R6=iPr, R7=iPr). 1H NMR (DMSO-d6), 7.48 (1H), 4.15-3.95 (4H),1.35-1.30 (24H).

Example 12 Diisopropyl(piperidin-1-ylmethylidene)ammoniumhexafluorophosphate (18, R6=iPr, R7=Piperidinyl)

A mixture of N,N-diisopropyllformamide (5 g) in anhydrousdichloromethane (40 mL) is added to a solution of phosphorus oxychloride(5.9 g) in dichloromethane (100 ml) at −78° C. The resulting mixture isstirred for 30 min at −78° C. The reaction mixture is then warmed toroom temperature and stirred for a further 2 h. The mixture is thencooled to 0° C. To this mixture, a solution of piperidine (3.3 g) andtriethylamine (3.92 g) in dichloromethane (50 ml) is added dropwise overa period of 30 min. The reaction mixture is then allowed to warm slowlyto room temperature and stirred for a further 2 h. The mixture is thenconcentrated in vacuo. Water (25 ml) is then added and the resultingmixture is cooled to 0° C. This mixture is then added to a cooledsolution of ammonium hexafluorophosphate (6.3 g) in water (25 ml). Theprecipitate is collected by filtration. The precipitate is washed withcold water (2×10 ml) and then with diethyl ether (10 ml). The materialis dried in vacuo and then recrystallised from acetone to givediisopropyl(piperidin-1-ylmethylidene)ammonium hexafluorophosphate (18,R6=iPr, R7=Piperidinyl) as a colourless solid. m.p. 239-240° C. 1H NMR(DMSO-d6), 7.83 (1H), 4.30-3.80 (2H), 3.64-3.59 (4H), 1.63-1.71 (6H),1.30-1.24 (12H).

The X-ray Structure of the obtained crystals is shown in FIG. 3.

Crystal Data [Recorded at 100(2) K]

Empirical formula C₁₂H₂₅F₆N₂P Formula weight 342.31 Crystal systemOrthorhombic Space group P212121 Cell parameters a = 9.315(2) Å b =12.051(2) Å c = 14.134(2) Å α = 90° β = 90° γ = 90° Volume of unit cell1586.6(5) Å³ Z^(*) 4 Calculated density 1.433 mg m⁻³ ^(*)(number ofasymmetric units in the unit cell)

Example 13 Tris(morpholino)methane (13, R6/R7=morpholino)

A mixture of triethylorthoformate (62.2 g), morpholine (54.5 g) andglacial acetic acid (1.26 g) is stirred at 180° C. for 5 h. During thistime, the ethanol formed is continuously removed by distillation. Thereaction mixture is left to cool to room temperature overnight. Theresulting precipitate is filtered and washed with heptane. The solid isre-crystallised using toluene to give tris(morpholino)methane, 13(R6/R7=morpholine). 1H NMR (CDCl₃), 3.66-3.60 (12H), 3.26 (1H),2.80-2.70 (12H).

Example 14 Tris(dimethylamino)methane (13, R6=Me, R7=Me),Tert-Butoxy-bis(dimethylamino)methane (14, R6=Me, R7=Me, R8=tBu) andN,N-Dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu)

Method 1

N,N,N′,N′-tetramethylformadinium methyl sufate (5 g) (prepared accordingto Example 1, X=MeSO₄) is added to a solution of potassium tert-butoxidein THF (23.6 ml, 1 M). The mixture is then stirred for 1 h at 60° C. Thereaction mixture is then filtered under argon. The mother liquor is thenconcentrated in vacuo to afford a residue (1.60 g) containing 13, 14 and15 (R6=Me, R7=Me, R8=tBu). 1H NMR (C₆D₆): 1.08, 1.16, 1.24, 2.29, 2.33,3.02, 4.06, 5.00. Relative amounts of 13 (R6=Me; R7=Me), 14 (R6=Me,R7=Me, R8=tBu), 15 (R6=Me, R7=Me, R8=Me) are determined by integrationof signals at 3.02, 4.06 and 5.00 ppm, respectively.

Method 2

N,N,N′,N′-tetramethylformadinium para-toluenesulfonate (500 mg)(prepared according to Example 2, X=4-MePhSO₃) is added to a solution ofpotassium tert-butoxide in THF (1.8 ml, 1 M). The mixture is thenstirred for 1 h at 50° C. The reaction mixture is then filtered underargon. The mother liquor is then concentrated in vacuo to afford aresidue containing 13, 14 and 15 (R6=Me, R7=Me, R8=tBu).

Method 3

N,N,N′,N′-tetramethylformadinium hexafluorophosphate (500 mg) (preparedaccording to Example 3, X═PF₆) is added to a solution of potassiumtert-butoxide in THF (2 ml, 1 M). The mixture is then stirred for 1 h at50° C. The reaction mixture is then filtered under argon. The motherliquor is then concentrated in vacuo to afford a residue containing 13,14 and 15 (R6=Me, R7=Me, R8=tBu).

Example 15 Tris(diethylamino)methane (13, R6=Et, R7=Et),Tert-Butoxy-bis(diethylamino)methane (14, R6=Et, R7=Et, R8=tBu) andN,N-Diethylformamide di-tert-butyl acetal (15, R6=Et, R7=Et, R8=tBu)

Method 1

N,N,N′,N′-tetraethylformadinium methyl sulfate (5 g) (prepared accordingto Example 4, X=MeSO₄) is added to a solution potassium tert-butoxide inTHF (18.7 ml, 1 M). The resulting mixture is then stirred for 1 h at 60°C. The reaction mixture is filtered under argon and the mother liquor isthen concentrated in vacuo to afford a residue (1.31 g) containing 13,14 and 15 (R6=Et, R7=Et, R8=tBu). 1H NMR (C₆D₆): 0.55-0.59, 0.81-0.85,0.98-1.06, 1.19, 1.24, 2.46-2.52, 2.64-2.80, 3.04-3.09, 3.80, 4.56,5.18. Relative amounts of 13 (R6=Et; R7=Et), 14 (R6=Et, R7=Et, R8=tBu),15 (R6=Et, R7=Et, R8=tBu) are determined by integration of signals at3.80, 4.56 and 5.18 ppm, respectively.

Method 2

N,N,N′,N′-tetraethylformadinium tetrafluoroborate (500 mg) (preparedaccording to Example 5, X═BF₄) is added to a solution of potassiumtert-butoxide in THF (2.05 ml, 1 M). The mixture is then stirred for 1 hat 50° C. The reaction mixture is then filtered under argon. The motherliquor is then concentrated in vacuo to afford a residue containing 13,14 and 15 (R6=Et, R7=Et, R8=tBu).

Method 3

N,N,N′,N′-tetraethylformadinium hexafluorophosphate (500 mg) (preparedaccording to Example 6, X═PF₆) is added to a solution of potassiumtert-butoxide in THF (1.66 ml, 1 M) The mixture is then stirred for 1 hat 50° C. The reaction mixture is then filtered under argon. The motherliquor is then concentrated in vacuo to afford a residue containing 13,14 and 15 (R6=Et, R7=Et, R8=tBu).

Example 16-1(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me)

Method 1

A mixture of 1 g(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) and 0.7 ml tris(dimethylamine)methane (13, R6=Me,R7=Me) (Aldrich, #221058) in toluene (5 ml) are heated for 16 h at 115°C. The mixture is concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 2

To 1 g (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) in solution in 5 ml toluene are added 3 gof tris(dimethylamino)methane (13, R6=Me, R7=Me) (Aldrich, #221058) and1 ml tert-butanol. The mixture is stirred at 80° C. for 24 h to yieldafter concentration to dryness nearly pure(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 3

To a mixture of 200 mg(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) and 0.49 ml tris(dimethylamino)methane (13, R6=Me,R7=Me) (Aldrich, #221058), tert-butanol (0.21 ml) is added. The mixtureis stirred at 80° C. for 24 h to yield after concentration to dryness(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 4

To a mixture of 200 mg(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) and 0.49 ml tris(dimethylamino)methane (13, R6=Me,R7=Me) (Aldrich, #221058), isobutyl alcohol (0.21 ml) is added. Themixture is stirred at 80° C. for 24 h to yield after concentration todryness(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 5

To a mixture of 200 mg(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) and 0.49 ml tris(dimethylamino)methane (13, R6=Me,R7=Me) (Aldrich, #221058), isopropyl alcohol (0.17 ml) is added. Themixture is stirred at 80° C. for 24 h to yield after concentration todryness(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 6

To a mixture of 200 mg(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) and 0.49 ml tris(dimethylamino)methane (13, R6=Me,R7=Me) (Aldrich, #221058), dimethoxyethane (0.2 ml) is added. Themixture is stirred at 80° C. for 24 h to yield after concentration todryness(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 7

Tert-butanol (0.67 g) is added to 1.65 g tris(dimethylamino)methane (13,R6=Me, R7=Me) (Aldrich, #221058) and the resulting mixture is stirredfor 1 h at 80° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (1.00 g) is added and the resulting mixture heatedat 80° C. for 8 h. The reaction mixture is cooled to room temperatureand concentrated in vacuo. Azeotropic distillation using toluene affords(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 8

1 g of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) is added to 10 g of a mixture containing13, 14 and 15 (R6=Me, R7=Me, R8=CMe₂Et) (prepared according to Example36, Method 1) and heated to 80° C. After 2 hours, the reaction is shownto be complete and is concentrated under vacuum to yield(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 9

N,N,N′,N′-tetramethylformamidinium methylsulfate (302 mg) (preparedaccording to Example 1) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.14 ml). The resulting mixture is thenstirred for 1 h at 50° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (100 mg) is then added and the mixture stirred at60° C. for 3 h. The mixture is then cooled to room temperature anddiluted by addition of 10 ml isopropyl acetate. The mixture is thenfiltered through silica and concentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 10

N,N,N′,N′-tetramethylformamidinium para-toluenesulfonate (1.93 g)(prepared according to Example 2) is added to a 1 M solution ofpotassium-tert-butoxide in THF (5.69 ml). The resulting mixture is thenstirred for 1 h at 50° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (500 mg) is then added and the mixture stirred at60° C. for 10 h. The mixture is then cooled to room temperature anddiluted by addition of 10 ml isopropyl acetate. The mixture is thenfiltered through silica and concentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 11

N,N,N′,N′-Tetramethylformamidinium hexafluorophosphate (1.75 g)(prepared according to Example 3) is added to a 1 M solution ofpotassium-tert-butoxide in THF (5.69 ml). The resulting mixture is thenstirred for 1 h at 50° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (500 mg) is then added and the mixture stirred at60° C. for 1 h. The mixture is then cooled to room temperature anddiluted by addition of 10 ml isopropyl acetate. The mixture is thenfiltered through silica and concentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 12

10 g (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) in 75 ml 1,2-dimethoxyethane. 17.8 mltert-butoxy-bis(dimethylamino)methane (14, R6=Me, R7=Me, R8=tBu) (Fluka#20425) is added and the mixture stirred overnight at 75° C. The mixtureis concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 13

A mixture of (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (1 g) and a mixture containing 13,14 and 15 (R6=Me, R7=Me, R8=tBu) (prepared according to Example 14,Method 1) are heated at 80° C. for 4 h. The mixture is then cooled toroom temperature and diluted by addition of 10 ml isopropyl acetate. Themixture is then filtered through silica and concentrated in vacuo toafford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 14

Mixture of 10 g (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) and 52 gtert-butoxy-bis(dimethylamino)methane (14, R6=Me, R7=Me, R8=tBu) isheated at 80° C. for 4 hours. The mixture is concentrated in vacuo togive(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 15

A mixture of 2 g(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) and 8.7 ml methoxy-bis(dimethylamine)methane (14,R6=Me, R7=Me, R8=Me) (Fluka #64875) is heated at 80° C. for 40 hours.The mixture is then concentrated in vacuo. The residue is dissolved inisopropyl acetate and passed through Kieselgel. The filtrate isconcentrated to give(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 16

A mixture of 1 g(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) and 1.2 ml N,N-dimethylformamide diisopropyl acetal(15, R6=Me, R7=Me, R8=iPr) (Aldrich #178535) are heated at 105° C.overnight. A further portion of N,N-dimethylformamide diisopropyl acetal(15, R6=Me, R7=Me, R8=iPr) is added and the mixture is stirred for 2days at 105° C. The mixture is then concentrated to give(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 17

To 0.2 g (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) in solution in 0.7 ml tetrahydrofuran areadded 0.4 g of tris(dimethylamino)methane (13, R6=Me, R7=Me) (Aldrich,#221058) and 0.17 ml tert-butanol. The mixture is stirred at 80° C. for8 h to yield after concentration to dryness to give(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 18

A mixture of 1 g(S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) and 3.4 ml N,N-dimethylformamide di-tert-butylacetal (15, R6=Me, R7=Me, R8=tBu) (Aldrich #358800) are heated at 50° C.overnight. The mixture is then concentrated to give(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 19

7 g of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) is added to 5.6 g of a mixture containing13, 14 and 15 (R6=Me, R7=Me, R8=CMe₂Et) (prepared according to Example36, Method 2) and heated to 85° C. The resulting mixture is stirred atthis temperature for 48 h. The mixture is then concentrated in vacuo togive(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 20

7 g of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) is added to 7.5 g of a mixture containing13, 14 and 15 (R6=Me, R7=Me, R8=CMe₂Et) (prepared according to Example36, Method 2) and heated to 85° C. The resulting mixture is stirred atthis temperature for 48 h. The mixture is then concentrated in vacuo togive(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 21

7 g of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) is added to 11.3 g of a mixturecontaining 13, 14 and 15 (R6=Me, R7=Me, R8=CMe₂Et) (prepared accordingto Example 36, Method 2) and heated to 85° C. The resulting mixture isstirred at this temperature for 24 h. The mixture is then concentratedin vacuo to give(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 22

7 g of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) is added to 18.8 g of a mixturecontaining 13, 14 and 15 (R6=Me, R7=Me, R8=CMe₂Et) (prepared accordingto Example 36, Method 2) and heated to 85° C. The resulting mixture isstirred at this temperature for 24 h. The mixture is then concentratedin vacuo to give(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 23

N,N,N′,N′-Tetramethylformamidinium hexafluorophosphate (350 mg)(prepared according to Example 3) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.1 ml). The resulting mixture is thenstirred for 1 h at room temperature.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (100 mg) is then added and the mixture is heated to55° C. The mixture is then stirred at this temperature for 3 h. Themixture is then cooled to room temperature and diluted by addition of 5ml isopropyl acetate. The mixture is then filtered through silica andconcentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 24

N,N,N′,N′-tetramethylformamidinium methylsulfate (302 mg) (preparedaccording to Example 1) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.1 ml). The resulting mixture is thenstirred for 1 h at 50° C. The mixture is then cooled to roomtemperature. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (302 mg) is then added and themixture is then stirred overnight. The mixture is then concentrated invacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 25

N,N,N′,N′-tetramethylformamidinium para-toluenesulfonate (1.9 g)(prepared according to Example 2) is added to a 1 M solution ofpotassium-tert-butoxide in THF (5.7 ml). The resulting mixture is thenstirred for 1 h at 50° C. The mixture is then cooled to roomtemperature. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (500 mg) is then added and themixture is then stirred overnight. The mixture is then concentrated invacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

Method 26

N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (1.75 g)(prepared according to Example 3) is added to a 1 M solution ofpotassium-tert-butoxide in THF (5.7 ml). The resulting mixture is thenstirred for 1 h at 50° C. The mixture is then cooled to roomtemperature. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (500 mg) is then added and themixture is then stirred overnight. The mixture is then concentrated invacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) as determined by hplc.

HPLC Method (Example 16-1, Methods 1-26)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

8-a (R1=Boc): 10.4 min 7-a (R1=Boc; R6=Me; R7=Me): 11.0 min Example 16-2Work-up/Purification of(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me)

(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) can be used directlyfrom the reaction or can be purified, as required. This optionalpurification step can be performed to remove solvents, reagents, and/orproducts generated from said reagents, for example.

Method 1

Solution of 7-a (R1=Boc; R6=Me; R7=Me) (0.2 g in 2 ml isopropyl acetate)prepared according to Example 16-1, Method 14. Activated charcoal (ca 50mg) is added and the mixture stirred at room temperature for 1 h. Themixture is filtered and concentrated in vacuo to give 7-a (R1=Boc;R6=Me; R7=Me) as determined by hplc. Spectroscopic data as for Example16-2, Method 7.

Method 2

Solution of 7-a (R1=Boc; R6=Me; R7=Me) (0.2 g in 2 ml isopropyl acetate)prepared according to Example 16-1, Method 14. Activated charcoal (ca 50mg) is added and the mixture stirred at reflux for 1 h. The mixture isfiltered and concentrated in vacuo to give 7-a (R1=Boc; R6=Me; R7=Me) asdetermined by hplc. Spectroscopic data as for Example 16-2, Method 7.

Method 3

Solution of 7-a (R1=Boc; R6=Me; R7=Me) (0.2 g in 2 ml isopropyl acetate)prepared according to Example 16-1, Method 14. The mixture is passedthrough a pad of Celite. The filtrate is then concentrated in vacuo togive 7-a (R1=Boc; R6=Me; R7=Me) as determined by hplc. Spectroscopicdata as for Example 16-2, Method 7.

Method 4

Solution of 7-a (R1=Boc; R6=Me; R7=Me) (0.2 g in 2 ml isopropyl acetate)prepared according to Example 16-1, Method 14. The mixture is passedthrough a pad of Kieselgel. The filtrate is then concentrated in vacuoto give 7-a (R1=Boc; R6=Me; R7=Me) as determined by hplc. Spectroscopicdata reported as for Example 16-2, Method 7.

Method 5

11 g of 7-a (R1=Boc; R6=Me; R7=Me) prepared according to Example 16-1,Method 14 is dissolved in 15 ml isopropyl acetate. The mixture is passedthrough a pad of Kieselgel and washed with isopropyl acetate (5×20 ml).The filtrate is concentrated in vacuo to give 7-a (R1=Boc; R6=Me; R7=Me)as determined by hplc. Spectroscopic data as for Example 16-2, Method 7.

Method 6

9 g of 7-a (R1=Boc; R6=Me; R7=Me) prepared according to Example 16-2,Method 5 is added toluene (50 ml). The solvent is then removed in vacuo.Further portions of toluene (3×50 ml) are added and the solventsuccessively removed in vacuo to give 7-a (R1=Boc; R6=Me; R7=Me) asdetermined by hplc. Spectroscopic data as for Example 16-2, Method 7.

Method 7

9 g of 7-a (R1=Boc; R6=Me; R7=Me) prepared according to Example 16-2,Method 6 is added heptane (15 ml). Solvent is removed in vacuo. Ethylacetate (5 ml) and the mixture is heated to 50° C. Heptane (10 ml) isadded. The mixture is then cooled to room temperature then concentratedin vacuo to give 7-a (R1=Boc; R6=Me; R7=Me). Spectroscopic data for 7-b(R1=Boc; R6=Me; R7=Me): R_(f) 0.49 (ethylacetate). δ_(H) (400 MHz; DMSO)1.48 (9H), 2.63 (2H), 2.79 (1H), 2.93 (6H), 3.06 (1H), 4.19 (1H), 6.96(1H), 7.32 (3H), 7.44 (2H), 7.63 (4H); m/z (ES+) 407.1 ([MH⁺, 71%), 351(100), 307 (41).

HPLC Method (Example 16-2, Methods 1-7)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 Min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

8-a (R1=Boc): 10.4 min 7-a (R1=Boc; R6=Me; R7=Me): 11.0 min Example 17(R)-5-Biphenyl-4-ylmethyl-3-[1-diethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et)

Method 1

A mixture of (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (1.41 g)tert-butoxy-bis(diethylamino)methane (14, R6=Et, R7=Et, R8=tBu) (3.76 g,prepared according to Example 15) is heated at 80° C. for 1 h. Themixture is then diluted with 10 ml isopropyl acetate and filteredthrough silica. The filtrate is then concentrated in vacuo andazeotroped successively with xylene (3×10 ml), toluene (3×10 ml),isopropyl acetate (3×10 ml) and diethyl ether (3×10 ml). Material isdried in vacuo to afford 1.54 g of(R)-5-biphenyl-4-ylmethyl-3-[1-diethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). R_(f) 0.41 (ethylacetate). δ_(H) (400 MHz, C₆D₆) 0.59 (6H), 1.63 (9H), 2.37 (2H), 2.44(4H), 2.59 (1H), 3.50 (1H), 4.46 (1H), 7.10-7.29 (6H), 7.42-7.45 (4H).

Method 2

N,N,N′,N′-tetraethylformamidinium methylsulfate (1.91 g, preparedaccording to Example 4) is added to a 1 M solution ofpotassium-tert-butoxide in THF (5.69 ml). The resulting mixture is thenstirred for 1 h at 50° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (500 mg) is then added and the mixture stirred at60° C. for 1 h. The mixture is then cooled to room temperature anddiluted by addition of 10 ml isopropyl acetate. The mixture is thenfiltered through silica and concentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-diethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). Spectroscopic data asfor Example 17, Method 1.

Method 3

N,N,N′,N′-tetraethylformamidinium tetrafluoroborate (347 mg, preparedaccording to Example 5) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.14 ml). The resulting mixture is thenstirred for 1 h at 50° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (100 mg) is then added and the mixture stirred at60° C. for 1 h. The mixture is then cooled to room temperature anddiluted by addition of 10 ml isopropyl acetate. The mixture is thenfiltered through silica and concentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-diethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). Spectroscopic data asfor Example 17, Method 1.

Method 4

N,N,N′,N′-Tetraethylformamidinium hexafluorophosphate (430 mg, preparedaccording to Example 6) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.14 ml). The resulting mixture is thenstirred for 1 h at 50° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (100 mg) is then added and the mixture stirred at60° C. for 1 h. The mixture is then cooled to room temperature anddiluted by addition of 10 ml isopropyl acetate. The mixture is thenfiltered through silica and concentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-diethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). Spectroscopic data asfor Example 17, Method 1.

Method 5

N,N,N′,N′-Tetraethylformamidinium hexafluorophosphate (430 mg) (preparedaccording to Example 6) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.1 ml). The resulting mixture is thenstirred for 1 h at room temperature.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (100 mg) is then added and the mixture is heated to55° C. The mixture is then stirred at this temperature for 3 h. Themixture is then cooled to room temperature and diluted by addition of 5ml isopropyl acetate. The mixture is then filtered through silica andconcentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-diethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). Spectroscopic data asfor Example 17, Method 1.

Method 6

N,N,N′,N′-tetraethylformamidinium methylsulfate (1.9 g) (preparedaccording to Example 4) is added to a 1 M solution ofpotassium-tert-butoxide in THF (5.7 ml). The resulting mixture is thenstirred for 1 h at 50° C. The mixture is then cooled to roomtemperature. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (500 mg) is then added and themixture is then stirred overnight. The mixture is then concentrated invacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-diethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). Spectroscopic data asfor Example 17, Method 1.

Method 7

N,N,N′,N′-tetraethylformamidinium hexafluorophosphate (430 mg) (preparedaccording to Example 6) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.1 ml). The resulting mixture is thenstirred for 1 h at 50° C. The mixture is then cooled to roomtemperature. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (100 mg) is then added and themixture is then stirred overnight. The mixture is then concentrated invacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). Spectroscopic data asfor Example 17, Method 1.

Method 8

N,N,N′,N′-tetraethylformamidinium tetrafluoroborate (347 mg) (preparedaccording to Example 5) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.1 ml). The resulting mixture is thenstirred for 1 h at 50° C. The mixture is then cooled to roomtemperature. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (100 mg) is then added and themixture is then stirred overnight. The mixture is then concentrated invacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). Spectroscopic data asfor Example 17, Method 1.

Method 9

N,N,N′,N′-tetraethylformamidinium tetrafluoroborate (347 mg) (preparedaccording to Example 5) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.1 ml). The resulting mixture is thenstirred for 1 h at 50° C. The mixture is then cooled to roomtemperature. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (100 mg) and ammoniumhexafluorophosphate (ca 1 mg) are then added and the mixture is thenstirred overnight. The mixture is then concentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et). Spectroscopic data asfor Example 17, Method 1.

Example 18(R)-5-Biphenyl-4-ylmethyl-3-[1-pyrrolidin-1-yl-meth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6/R7=Pyrrolidinyl)

Method 1

A mixture of 1-pyrrolidin-1-ylmethylenepyrrolidinium methylsulfate (18.5g, prepared according to Example 7) and potassium tert-butoxide (6.3 g)in toluene (40 ml) are stirred for 1 h.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (5 g) is added and the mixture heated to 80° C.After 1.5 h, the mixture is cooled to room temperature, diluted withisopropyl acetate and filtered through silica to give (7-a, R1=Boc,R6/R7=Pyrrolidinyl). Purification by chromatography (isopropyl acetate)gives(R)-5-biphenyl-4-ylmethyl-3-[1-pyrrolidin-1-yl-meth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6/R7=Pyrrolidinyl). R_(f) 0.32(ethyl acetate). δ_(H) (400 MHz, DMSO) 1.50 (9H), 1.80 (4H), 2.62 (1H),2.71 (1H), 2.82 (1H), 3.06 (1H), 3.46 (4H), 4.19 (1H), 7.19 (1H), 7.34(2H), 7.36 (1H), 7.46 (2H), 7.62 (2H), 7.65 (2H). m/z (ES+) 433 ([MH]⁺,100%), 377 (64), 333 (36).

Method 2

A mixture of 1-pyrrolidin-1-ylmethylene-pyrrolidiniumhexafluorophosphate (424 mg, prepared according to Example 8) andpotassium tert-butoxide (1 M in THF, 1.1 ml) are stirred for 1 h at 50°C. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) (0.1 g) is added and the mixture heatedto 60° C. After 1.5 h, the mixture is cooled to room temperature,diluted with isopropyl acetate and filtered through silica to give(R)-5-biphenyl-4-ylmethyl-3-[1-pyrrolidin-1-yl-meth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6/R7=Pyrrolidinyl). Spectroscopicdata as for Example 18, Method 1.

Method 3

A mixture of 1-pyrrolidin-1-ylmethylenepyrrolidinium methylsulfate (380mg, prepared according to Example 7) and sodium tert-butoxide (0.1 ml)in toluene are stirred overnight.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (100 mg) is added and the mixture heated to 80° C.After 4 h, the mixture is cooled to room temperature and concentrated invacuo to give (7-a, R1=Boc, R6/R7=Pyrrolidinyl). Spectroscopic data asfor Example 18, Method 1.

Method 4

1-Pyrrolidin-1-ylmethylene-pyrrolidinium hexafluorophosphate (424 mg)(prepared according to Example 8) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.1 ml). The resulting mixture is thenstirred for 1 h at room temperature.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (100 mg) is then added and the mixture is heated to55° C. The mixture is then stirred at this temperature for 3 h. Themixture is then cooled to room temperature and diluted by addition of 5ml isopropyl acetate. The mixture is then filtered through silica andconcentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-pyrrolidin-1-yl-meth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6/R7=Pyrrolidinyl). Spectroscopicdata as for Example 18, Method 1.

Method 5

1-Pyrrolidin-1-ylmethylene-pyrrolidinium hexafluorophosphate (424 mg)(prepared according to Example 8) is added to a 1 M solution ofpotassium-tert-butoxide in THF (1.1 ml). The resulting mixture is thenstirred for 1 h at 50° C. The mixture is then cooled to roomtemperature. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) (100 mg) is then added and themixture is then stirred overnight. The mixture is then concentrated invacuo to afford((R)-5-biphenyl-4-ylmethyl-3-[1-pyrrolidin-1-yl-meth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6/R7=Pyrrolidinyl). Spectroscopicdata as for Example 18, Method 1.

Example 19(R)-5-Biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr)

Method 1

A 1 M solution of potassium tert-butoxide in THF (11.7 ml) is added todiisopropyl(piperidin-1-ylmethylidene)ammonium hexafluorophosphate (5 g,prepared according to Example 12). The resulting mixture is then stirredfor 1 h at 50° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (1 g) is then added to the reaction and theresulting mixture is stirred for 1 h at room temperature. The mixture isdiluted with isopropyl acetate and filtered through silica. The residueis concentrated in vacuo then purified by column chromatography (ethylacetate) to give(R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). R_(f) 0.55 (ethylacetate). 1H NMR (DMSO-d6), 7.65-7.62 (2H), 7.61-7.58 (2H), 7.47-7.42(2H), 7.37-7.31 (1H), 7.29-7.25 (2H), 7.01 (1H), 4.28-4.20 (1H),3.84-3.70 (2H), 3.07-3.01 (1H), 2.82-2.73 (1H), 2.71-2.63 (1H) 2.49-2.44(1H), 1.49 (9H), 1.13-1.08 (12H).

Method 2

N,N,N′,N′-tetraisopropylformamidinium tetrafluoroborate (2.13 g,prepared according to Example 11) is added to a 1 M solution ofpotassium-tert-butoxide in THF (5.69 ml). The resulting mixture is thenstirred for 1 h at 50° C.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (500 mg) is then added and the mixture stirred at60° C. for 1 h. The mixture is then cooled to room temperature anddiluted by addition of 10 ml isopropyl acetate. The mixture is thenfiltered through silica and concentrated in vacuo to afford(R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). Spectroscopic dataas for Example 19, Method 1.

Example 20(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylamino-meth-(E/Z)-ylidene]-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(7-a, R1=Piv, R6=Me, R7=Me)

A mixture of(S)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethyl-propionyl)-pyrrolidin-2-one(8-a, R1=Piv) (1.0 g, 3 mmol) and tert-butoxy-bis(dimethylamino)methane(14, R6=Me, R7=Me, R8=tBu) (Fluka #20425) (5.5 g) are stirred at 80° C.for 17 h. The mixture is then cooled to room temperature andconcentrated in vacuo. The residue is then dissolved in isopropylacetate and filtered through Kieselgel. The filtrate is concentrated invacuo to give(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylamino-meth-(E/Z)-ylidene]-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(7-a, R1=Piv, R6=Me, R7=Me). δ_(H) (400 MHz; DMSO) 1.31 (9H), 2.57 (1H),2.70 (1H), 2.81 (1H) 2.98 (6H), 3.00 (1H), 4.40 (1H), 7.06 (1H), 7.33(3H), 7.45 (2H), 7.60 (2H), 7.65 (2H). m/z (ES+) 391 ([MH]⁺, 100%).

Example 21(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc)

Method 1

(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (1 g, 2.5 mmol) isdissolved in THF (5 ml) and cooled to 0° C. aq. Hydrochloric acid (37%;0.2 ml) is added followed by water (2.1 ml). Mixture is stirred at roomtemperature for 1.5 h. The phases are separated and the organic phasedried (MgSO₄) and concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc). δ_(H) (400 MHz, DMSO) 1.51 (9H),2.40 (1H), 2.50 (1H), 2.67 (1H), 3.11 (1H), 4.34 (1H), 7.26 (3H), 7.42(2H), 7.58 (4H), 10.27 (1H); δ_(H) (400 MHz; CDCl₃) 1.53, 1.76-1.80,1.88-1.96, 2.27-2.33, 2.35-2.43, 2.49-2.61, 2.80-2.86, 3.00-3.11,3.16-3.21, 3.51-3.54, 3.65-3.70, 4.25-4.36, 7.15-7.20, 7.26-7.30,7.34-7.39, 7.46-7.53, 9.74 (0.4H), 9.75 (0.2H), 10.86 (0.4H). m/z (+)380 ([MH]⁺, 5%), 324 (100).

Method 2

(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et) (1 g) is dissolved inTHF (6.9 ml) and cooled to 10-15° C. A solution of concentrated sulfuricacid (0.09 ml) in water (3 ml) is added. Mixture is stirred at roomtemperature for 1.5 h. The phases are separated and the aqueous phase isextracted with isopropyl acetate. The combined organic phases are dried(MgSO₄) and concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc). R_(f) 0.49 (ethyl acetate).Spectroscopic data as for Example 21, Method 1.

Method 3

(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Et, R7=Et) (32.5 g) is dissolvedin THF (190 ml) at 60° C. The mixture is then cooled to 10-15° C. Anaqueous solution of 1 M sulfuric acid (96 ml) is added over a period of30 min, giving a solution pH 2. Mixture is stirred at room temperaturefor 0.5 h. The phases are separated and the organic phase washed with 1M potassium carbonate solution (50 ml). The phases are separated. Theorganic phase is dried (MgSO₄) and concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc). R_(f) 0.49 (ethyl acetate).Spectroscopic data as for Example 21, Method 1.

Example 22 Enol form:(R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-[1-hydroxymeth-(E,Z)-ylidene]pyrrolidin-2-one(6-a, R1=Piv)

(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Piv, R6=Me, R7=Me) (927 mg) is dissolvedin THF (5 ml) and cooled to 10° C. Hydrochloric acid (1 M; 2.6 ml) isadded followed by water (2.1 ml). Mixture is stirred at room temperaturefor 17 h. The mixture is diluted with ethyl acetate (5 ml) and thephases separated. The organic phase is washed with water, brine thendried (MgSO₄). Concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-[1-hydroxymeth-(E,Z)-ylidene]pyrrolidin-2-one(6-a, R1=Piv). δ_(H) (400 MHz; DMSO) 1.31 (9H), 2.43 (1H), 2.50 (2H),3.01 (1H), 4.53 (1H), 7.28 (2H), 7.35 (1H), 7.45 (2H), 7.61 (2H), 7.64(2H); m/z (ES+) 364 ([MH]⁺, 100%).

Example 23(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc)

Method 1

(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (7 g) is added to THF(210 ml) and the resulting mixture cooled to −78° C. Diisobutylaluminiumhydride (109 ml, 103 mmol; 0.95 M in THF) is added over 1.5 h. To themixture is then added Rochelle's Salt (430 ml; 1.2 M in water) and themixture stirred vigorously. Ethyl acetate (400 ml) is added and thephases are separated. The organic phase is concentrated in vacuo. Theresulting residue is dissolved in ethyl acetate (20 ml) and washed withbrine (20 ml). Phases are separated. The organic phase is thenconcentrated in vacuo. Diethyl ether (50 ml) is added, filtered and thefiltrate concentrated to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc).

Crude(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) can be optionally purified by columnchromatography eluting with 3:1 heptane/ethyl acetate. 1H NMR: δ_(H)(400 MHz, CDCl₃) 1.62 (9H), 2.56 (1H), 2.60 (1H), 2.70 (1H), 3.26 (1H),4.43 (1H), 5.45 (1H), 6.17 (1H), 7.26 (2H), 7.34 (1H), 7.44 (2H), 7.54(2H), 7.57 (2H); m/z (+ESI) 381 ([MNa]⁺, 7%), 364 ([MH]⁺, 12), 308(100), 264 (10).

(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) is a crystalline solid and can becharacterised by single crystal X-ray analysis and X-ray powderpatterns. Reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 4.7, 9.3, 10.5, 13.3, 13.9, 15.3,16.9, 18.0, 18.6, 19.6, 20.9, 21.8, 22.9, 23.3, 27.5, 28.1, 30.7, 34.9.The most intensive reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 4.6, 10.5, 13.3, 13.9, 16.9, 18.6,19.6, 20.9. Data taken using a Bruker D8 Advance diffractometer usingCu—Kα radiation.

The X-ray Structure of the obtained crystals is shown in FIG. 4. Singlecrystal for this determination is obtained from methanol/water assolvent.

Crystal Data [Recorded at 100(2) K]

Empirical formula C₂₃H₂₅NO₃ Formula weight 363.44 Crystal systemMonoclinic Space group P21 Cell parameters a = 11.512(2) Å b = 9.197(2)Å c = 19.002(3) Å α = 90° β = 94.737(7)° γ = 90° Volume of unit cell2005.0(6) Å³ Z^(*) 4 Calculated density 1.204 mg m⁻³ ^(*)(number ofasymmetric units in the unit cell)

Method 2

(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (100 mg, 0.25 mmol) isadded to THF (0.5 ml) at 0° C. Sodium triacetoxyborohydride (111 mg,0.50 mmol) is then added. The mixture is stirred for 1 h then stirred atroom temperature overnight. Water (5 ml) is added and then extractedwith toluene. Organic phase dried (MgSO₄) and concentrated in vacuo togive(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example23, Method 1.

Example 24(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc)

Method 1

Crude(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (67.5 g) is dissolvedin THF (340 ml) and cooled to 0° C. Hydrochloric acid (37%; 13.1 ml) isadded followed by water (143.4 ml). Mixture is stirred at roomtemperature for 2 h. Phases are separated. To the organic phase is addedformaldehyde solution (37% in water; 138 ml). Potassium carbonate (31.8g) is added portionwise over 4 h. 1% Tetra-n-butylammoniumhydroxidesolution (14.2 ml) is added followed by sodium hydroxide solution (30%in water) until pH 10.5. The mixture is stirred for 2 h. The phases areseparated. The organic phase is washed with water (100 ml) and sodiumbisulfite (20 g) added. Toluene (100 ml) and sodium chloride solution(20%; 50 ml). The phases are separated. The organic phase is extractedwith a sodium chloride solution (20%; 50 ml), dried (Na₂SO₄) andconcentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) (63 g). The material can berecrystallised as follows: crude(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) (58.4 g) is dissolved in methanol(525 ml) at 50° C. Water (175 ml) is added and the mixture is cooled to0° C. The solid is collected by filtration and the cake washed with amixture of methanol (53 ml) and water (18 ml). The solid is then driedin vacuo, giving(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as Example 23.

Method 2

Crude(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (66.7 g) is dissolvedin THF (340 ml) and cooled to 10° C. Sulphuric acid (96%; 6.9 ml) isadded followed by water (152 ml). The mixture is stirred at roomtemperature for 0.5 h. Phases are separated. The organic phase is addedto formaldehyde solution (37% in water; 138 ml). 1%Tetra-n-butylammoniumhydroxide solution (14.2 ml) is added. Potassiumcarbonate (27.8 g) is added portionwise over 0.5 h. Sodium hydroxidesolution (15.1 g) is added over 3 h, maintaining pH 10.5. The phases areseparated. The organic phase is washed with water (100 ml) followed bysodium bisulfite solution (21.4 g). Toluene (100 ml) and sodium chloridesolution (50 ml) added. The phases are separated. The organic phase isextracted with sodium chloride solution (20%; 50 ml), dried (Na₂SO₄) andconcentrated in vacuo to give(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) (63 g). Material can berecrystallised as follows: crude(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) (58.4 g) is dissolved in methanol(525 ml) at 50° C. Water (175 ml) is added and the mixture is cooled to0° C. The solid is collected by filtration and the cake washed with amixture of methanol (53 ml) and water (18 ml). The solid is then driedin vacuo, giving(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as in Example23.

HPLC Method (Example 24)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

6-a (R1=Bob): 2.62 min 7-a (R1=Boc; R6=Me; R7=Me): 11.0 min 4-a(R1=Boc): 12.0, min Example 25(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) and (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc)

Method 1

2.0 g of crude(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in 10 ml THF is submitted to reactwith 5.0 g 37% aq. formaldehyde solution and 0.7 g sodium carbonate.After 1 h stirring at room temperature the aqueous phase is removed. Theorganic phase is diluted with toluene, washed with water andconcentrated to dryness to yield an oily residue. The latter is thensubmitted to a silica-gel chromatography (100 g silicagel Merck),eluting with a mixture 1:1 of ethyl and isopropyl acetate to separate(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) and (3R/S,5S)-5-biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc).

Spectroscopic data for(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as in Example 23.

Spectroscopic data for (3R/S,5S)-5-biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc): δ_(H) (400 MHz, DMSO) 1.51 (9H),1.89 (1H), 1.98 (1H), 2.55 (1H), 2.85 (1H), 3.50-2.62 (2H), 4.24-4.30(1H), 4.45 (1H), 7.28-7.34 (3H), 7.41-7.45 (2H), 7.58-7.63 (4H); m/z(ES+) 382 ([MH]⁺, 9%), 326 (100), 282 (12).

Method 2

1 g(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to THF (2.5 ml) at roomtemperature. 37% Formaldehyde solution (1.3 ml) is then added. Potassiumcarbonate (0.28 g) is then added portionwise and the resulting mixtureis then stirred for 72 h at room temperature. Water (1 ml) and sodiumbisulfite solution (0.5 ml) are subsequently'added. The phases areseparated and organic phase dried (MgSO₄). The mixture is concentratedin vacuo to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) and 20% (5-a, R1=Boc) (by nmr).Spectroscopic data as for Example 25, Method 1.

Method 3

7.4 g(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) dissolved in 50 ml THF are mixedtogether with 4.4 g 37% aq. formaldehyde solution, 0.13 gtetrabutylammonium hydroxide 40% solution and 40 ml potassium carbonate1 M solution. After 1 h stirring at 40° C., the two phases areseparated. The organic phase is diluted with 50 ml toluene andconcentrated under vacuum to about 20 ml. The residue is again dilutedwith 85 ml toluene. 2.4-diazabicycloundecene is added followed with 0.42g methanesulfonyl chloride. After 1 h at room temperature, 10 ml waterwere added and the mixture acidified with several drops of sulfuricacid. The aqueous phase is removed, the organic phase washed with 10 mlof water and concentrated under vacuum to dryness. The residue isdissolved in 100 ml methanol at 50° C. and saturated at the sametemperature with 25 ml water. The suspension is afterwards cooled to 0°C., filtered, washed with 12 ml methanol/water 2:1 and dried undervacuum to yield(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example25, Method 1.

Method 4

A mixture of potassium carbonate solution in water (1 M, 2.3 ml),tetrabutylammonium hydroxide solution (40%, 0.01 ml) and formaldehydesolution (37% in water, 0.32 ml) is added to(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc). The resulting mixture is stirredrapidly and heated to 50° C. After 4 h, the mixture is cooled to roomtemperature and concentrated in vacuo. R_(f) (ethyl acetate): 0.77 (4-a,R1=Boc); 0.44 (5-a, R1=Boc). Spectroscopic data as for Example 25,Method 1.

Method 5

To a solution of(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in THF (3.8 g) (prepared accordingto Example 21, Method 3) is added potassium carbonate (2.8 g in 20 mlwater), tetrabutylammonium hydroxide solution (40%, 0.03 g) andformaldehyde solution (37% in water, 2.2 ml) to give a solution of pH11. The mixture is then stirred for 2 h at 45° C. The mixture is thencooled to room temperature and the phases are separated. The organicphase is diluted with toluene (20 ml) and washed with sodium bisulfitesolution (20 ml, 40%) and then brine (20 ml). The organic phase is thendried (MgSO₄) and concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example25, Method 1.

Method 6

To a solution of(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in THF (3.8 g) (prepared accordingto Example 21, Method 3) is added potassium carbonate (2.8 g in 20 mlwater), tetrabutylammonium hydroxide solution (40%, 0.03 g) and chloral(4.4 g) to give a solution of pH 11. The mixture is then stirred for 2 hat 45° C. The mixture is then cooled to room temperature and the phasesare separated. The organic phase is diluted with toluene (20 ml) andwashed with sodium bisulfite solution (20 ml, 40%) and then brine (20ml). The organic phase is then dried (MgSO₄) and concentrated in vacuoto give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example25, Method 1.

Method 7

To a solution of(R)-5-Biphenyl-4-ylmethyl-3,1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in THF (3.8 g) (prepared accordingto Example 21, Method 3) is added aqueous potassium carbonate (0.2 ml, 1M), tetrabutylammonium hydroxide solution (40%, 0.07 g) and formaldehydesolution (37 in water, 2.2 ml) to give a solution of pH 8. The mixtureis then stirred for 2 h at 45° C. The mixture is then cooled to roomtemperature and the phases are separated. The organic phase is dilutedwith toluene (20 ml) and washed with sodium bisulfite solution (20 ml,40%) and then brine (20 ml). The organic phase is then dried (MgSO₄) andconcentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example25, Method 1.

Method 8

To a solution of(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in THF (3.8 g) (prepared accordingto Example 21, Method 3) is added a 1 M aqueous sodium formate solution(20 ml), tetrabutylammonium hydroxide solution (40%, 0.07 g) andformaldehyde solution (37% in water, 2.2 ml) to give a solution of pH 7.The mixture is then stirred for 4 h at 45° C. The mixture is then cooledto room temperature and the phases are separated. The organic phase isdiluted with toluene (20 ml) and washed with sodium bisulfite solution(20 ml, 40%) and then brine (20 ml). The organic phase is then dried(MgSO₄) and concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example25, Method 1.

Method 9

To a solution of(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in THF (3.8 g) (prepared accordingto Example 21, Method 3) is added a 1 M aqueous sodium acetate solution(20 ml), tetrabutylammonium hydroxide solution (40%, 0.07 g) andformaldehyde solution (37% in water, 2.2 ml) to give a solution of pH 8.The mixture is then stirred for 4 h at 45° C. The mixture is then cooledto room temperature and the phases are separated. The organic phase isdiluted with toluene (20 ml) and washed with sodium bisulfite solution(20 ml, 40%) and then brine (20 ml). The organic phase is then dried(MgSO₄) and concentrated in vacuo to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example25, Method 1.

Method 10

To a mixture of 3.79 g(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in tetrahydrofuran (0.4 M solution)is added potassium carbonate (20 ml, 1 M solution in water) andtetrabutylammonium hydroxide (0.07 ml, 40% wt in water). Formaldehyde(2.2 ml, 37% wt in water) is then added to the mixture. The resultingmixture is stirred for 2 h at 45° C. The phases are separated. Theorganic phase is diluted with toluene (20 ml). The organic phase is thenwashed with sodium bisulfite solution (20 ml, 40% wt in water) and thenwith brine (5 ml). The separated organic phase is then dried (MgSO₄) andconcentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 11

To a mixture of 3.79 g(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in tetrahydrofuran (0.4 M solution)is added potassium carbonate (20 ml, 1 M solution in water) andtetrabutylammonium hydroxide (0.07 ml, 40% wt in water). Formaldehyde(2.2 ml, 37% wt in water) is then added to the mixture. The pH of themixture is adjusted to pH 14 by the addition of a sodium hydroxidesolution (1 M in water). The resulting mixture is stirred for 2 h at 45°C. The phases are separated. The organic phase is diluted with toluene(20 ml). The organic phase is then washed with sodium bisulfite solution(20 ml, 40% wt in water) and then with brine (5 ml). The separatedorganic phase is then dried (MgSO₄) and concentrated under reducedpressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 12

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).Sodium hydrogen carbonate (1.05 ml, 1 M solution in water) andtetrabutylammonium hydroxide (3.5 μl, 40% wt in water) are added to themixture. Formaldehyde (0.12 ml, 37% wt in water) is then added to themixture. The resulting mixture is stirred for 2 h at 45° C. The phasesare separated. The organic phase is diluted with toluene (5 ml). Theorganic phase is then washed with sodium bisulfite solution (5 ml, 40%wt in water) and then with brine (5 ml). The separated organic phase isthen dried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 13

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).Cesium carbonate (1.05 ml, 1 M solution in water) and tetrabutylammoniumhydroxide (3.5 μl, 40% wt in water) are added to the mixture.Formaldehyde (0.12 ml, 37% wt in water) is then added to the mixture.The resulting mixture is stirred for 2 h at 45° C. The phases areseparated. The organic phase is diluted with toluene (5 ml). The organicphase is then washed with sodium bisulfite solution (5 ml, 40% wt inwater) and then with brine (5 ml). The separated organic phase is thendried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 14

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).Sodium carbonate (1.05 ml, 1 M solution in water) and tetrabutylammoniumhydroxide (3.5 μl, 40% wt in water) are added to the mixture.Formaldehyde (0.12 ml, 37% wt in water) is then added to the mixture.The resulting mixture is stirred for 2 h at 45° C. The phases areseparated. The organic phase is diluted with toluene (5 ml). The organicphase is then washed with sodium bisulfite solution (5 ml, 40% wt inwater) and then with brine (5 ml). The separated organic phase is thendried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 15

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).Potassium carbonate (1.05 ml, 1 M solution in water) andtetrabutylammonium hydroxide (3.5 μl, 40% wt in water) are added to themixture. Formaldehyde (0.12 ml, 37% wt in water) is then added to themixture. The resulting mixture is stirred for 2 h at 45° C. The phasesare separated. The organic phase is diluted with toluene (5 ml). Theorganic phase is then washed with sodium bisulfite solution (5 ml, 40%wt in water) and then with water (5 ml). The separated organic phase isthen dried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 16

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).Dimethylsulfoxide (1 ml) is then added. Potassium carbonate (1.05 ml, 1M solution in water) and tetrabutylammonium hydroxide (3.5 μl, 40% wt inwater) are added to the mixture. Formaldehyde (0.12 ml, 37% wt in water)is then added to the mixture. The resulting mixture is stirred for 2 hat 45° C. The phases are separated. The organic phase is diluted withtoluene (5 ml). The organic phase is then washed with sodium bisulfitesolution (5 ml, 40% wt in water) and then with water (5 ml). Theseparated organic phase is then dried (MgSO₄) and concentrated underreduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 17

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).1-Methyl-2-pyrrolidinone (1 ml) is then added. Potassium carbonate (1.05ml, 1 M solution in water) and tetrabutylammonium hydroxide (3.5 μl, 40%wt in water) are added to the mixture. Formaldehyde (0.12 ml, 37% wt inwater) is then added to the mixture. The resulting mixture is stirredfor 2 h at 45° C. The phases are separated. The organic phase is dilutedwith toluene (5 ml). The organic phase is then washed with sodiumbisulfite solution (5 ml, 40% wt in water) and then with water (5 ml).The separated organic phase is then dried (MgSO₄) and concentrated underreduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 18

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 ml) is then added.Potassium carbonate (1.05 ml, 1 M solution in water) andtetrabutylammonium hydroxide (3.5 μl, 40% wt in water) are added to themixture. Formaldehyde (0.12 ml, 37% wt in water) is then added to themixture. The resulting mixture is stirred for 2 h at 45° C. The phasesare separated. The organic phase is diluted with toluene (5 ml). Theorganic phase is then washed with sodium bisulfite solution (5 ml, 40%wt in water) and then with water (5 ml). The separated organic phase isthen dried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 19

To a mixture of 200 mg(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) in tetrahydrofuran (2 ml) is addedformaldehyde (0.12 ml, 37% wt in water) and tetrabutylammonium hydroxide(3.5 μl, 40% wt in water). The pH of the mixture is adjusted to pH 9 bythe addition of a potassium carbonate solution (1 M in water). Theresulting mixture is stirred for 2 h at 45° C. The phases are separated.The organic phase is diluted with toluene (5 ml). The organic phase isthen washed with sodium bisulfite solution (5 ml, 40% wt in water) andthen with water (5 ml). The separated organic phase is then dried(MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 20

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to acetonitrile (2 ml).Potassium carbonate (1.05 ml, 1 M solution in water) andtetrabutylammonium hydroxide (3.5 μl 40% wt in water) are added to themixture. Formaldehyde (0.12 ml, 37% wt in water) is then added to themixture. The resulting mixture is stirred for 2 h at 45° C. The phasesare separated. The organic phase is diluted with toluene (5 ml). Theorganic phase is then washed with sodium bisulfite solution (5 ml, 40%wt in water) and then with water (5 ml). The separated organic phase isthen dried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 21

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to acetone (2 ml).Potassium carbonate (1.05 ml, 1 M solution in water) andtetrabutylammonium hydroxide (3.5 μl 40% wt in water) are added to themixture. Formaldehyde (0.12 ml, 37% wt in water) is then added to themixture. The resulting mixture is stirred for 2 h at 45° C. The phasesare separated. The organic phase is diluted with toluene (5 ml). Theorganic phase is then washed with sodium bisulfite solution (5 ml, 40%wt in water) and then with water (5 ml). The separated organic phase isthen dried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 22

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tertiary-butanol (2 ml).Potassium carbonate (1.05 ml, 1 M solution in water) andtetrabutylammonium hydroxide (3.5 μl, 40% wt in water) are added to themixture. Formaldehyde (0.12 ml, 37% wt in water) is then added to themixture. The resulting mixture is stirred for 2 h at 45° C. The mixtureis diluted with water (5 ml) and ethyl acetate (5 ml). The phases areseparated. The organic phase is then washed with sodium bisulfitesolution (5 ml, 40% wt in water) and then with water (5 ml). Theseparated organic phase is then dried (MgSO₄) and concentrated underreduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 23

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).Potassium carbonate (1.05 ml, 1 M solution in water) andtetrabutylammonium hydroxide (3.5 μl, 40% wt in water) are added to themixture. Formaldehyde (0.10 ml, 37% wt in water) is then added to themixture. The resulting mixture is stirred for 2 h at 45° C. The phasesare separated. The organic phase is diluted with ethyl acetate (5 ml).The organic phase is then washed with sodium bisulfite solution (5 ml,40% wt in water) and then with water (5 ml). The separated organic phaseis then dried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

Method 24

200 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to tetrahydrofuran (2 ml).Potassium carbonate (1.05 ml, 1 M solution in water) andtetrabutylammonium hydroxide (3.5 μl, 40% wt in water) are added to themixture. Formaldehyde (0.16 ml, 37% wt in water) is then added to themixture. The resulting mixture is stirred for 2 h at 45° C. The phasesare separated. The organic phase is diluted with ethyl acetate (5 ml).The organic phase is then washed with a sodium bisulfite solution (5 ml,40% wt in water) and then with water (5 ml). The separated organic phaseis then dried (MgSO₄) and concentrated under reduced pressure to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as determined by hplc.

HPLC Method (Example 25, Methods 1-24)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

6-a (R1=Boc): 2.62 min 5-a (R1=Boc): 8.39 min 4-a (R1=Boc): 12.0 minExample 26(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc)

50 g (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) and 261 g Bredereck's reagent (14, R6=Me,R7=Me, R8=tBu) are stirred at 80° C. for 24 h and concentratedafterwards under vacuum to yield 67.5 g of a viscous residue. The lateris dissolved in 340 ml THF and mixed with 13.1 ml hydrochloric acid 37%in 143 ml water. After 1 h stirring at room temperature, the loweraqueous phase is removed, and 150.2 g aqueous formaldehyde 37% is addedfollowed with 30 g potassium carbonate added portions wise at 20-25° C.Again after 3 hour stirring, the aqueous phase is removed. The remainingorganic phase is diluted with 100 ml toluene, washed with 50 ml brineand concentrated under vacuum to leave 58.4 g of a viscous residue. Thelatter is dissolved in 525 ml methanol at 50° C., and saturated at thesame temperature with 175 ml water. The resulting suspension is cooledto 0° C., filtered to collect the crystals, washed with 60 mlmethanol/water 2:1 and dried under vacuum to yield of white crystals of(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as in Example23.

HPLC Method (Example 26)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

6-a (R1=Boc): 2.62 min 8-a (R1=Boc): 10.4 min 7-a (R1=Boc; R6=Me;R7=Me): 11.0 min 4-a (R1=Boc): 12.0 min Example 27(R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylenepyrrolidin-2-one(4-a, R1=Piv)

(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Piv) (680 mg) is dissolved in THF (3.5ml) at room temperature. Formaldehyde solution (1.8 ml, 37% in water) isadded followed by the portionwise addition of potassium carbonate (388mg). The mixture is then stirred for 70 h. Water (1 ml) and sodiumbisulfite solution (0.5 ml) are subsequently added. The phases areseparated and organic phase dried (MgSO₄). The crude material ispurified by chromatography (heptane/ethyl acetate, 10:1) to give(R)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylenepyrrolidin-2-one(4-a, R1=Piv). δ_(H) (400 MHz, DMSO) 1.34 (9H), 2.55-2.64 (2H), 2.70(1H), 3.26 (1H), 4.59 (1H), 5.55 (1H), 5.98 (1H), 7.26 (2H), 7.34 (1H),7.44 (2H), 7.53-7.58 (4H). m/z (ES+) 348 ([MH]⁺, 100%).

Example 28 (R)-5-Biphenyl-4-ylmethyl-3-methylenepyrrolidin-2-one (4-a,R1=H)

(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) (509 mg) is dissolved indichloromethane (10 ml). Mixture is cooled to 0° C. and trifluoroaceticacid (0.5 ml) is added. The mixture is then stirred for 2 h thenextracted with saturated sodium carbonate solution (20 ml). Phases areseparated. The organic phase is dried (MgSO₄) and concentrated to give(R)-5-biphenyl-4-ylmethyl-3-methylenepyrrolidin-2-one (4-a, R1=H). δ_(H)(400 MHz, DMSO) 2.47 (1H), 2.68 (1H), 2.74 (1H), 2.87 (1H), 3.87 (1H),5.22 (1H), 5.64 (1H), 7.33 (3H), 7.45 (2H), 7.60 (2H), 7.65 (2H), 8.32(1H); m/z (+) 264 ([MH]⁺, 100%); m/z (+ESI) 264 ([MH]⁺, 100%).

(R)-5-Biphenyl-4-ylmethyl-3-methylenepyrrolidin-2-one (4-a, R1=H) is acrystalline solid and can be characterised by an X-ray powder pattern.Reflections in the X-ray diffraction pattern show the followinginterlattice plane intervals (average 2θ in [°] are indicated with errorlimit of ±0.2): 2θ in [°]: 7.1, 13.3, 13.7, 14.5, 16.6, 17.7, 18.2,19.4, 21.4, 22.5, 23.6, 24.0, 26.5, 27.6, 29.1, 29.9. Data taken using aBruker D8 Advance diffractometer using Cu—Kα radiation.

HPLC Method (Example 28)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

4-a (R1=H): 5.70 min 4-a (R1=Boc): 12.0 min Example 29(3R/S,5S)-5-Biphenyl-4-ylmethyl-3-dimethoxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=Me, R9=Me, Y═O)

1.1 g(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is dissolved in 12 mlof methanol. HCl in methanol (prepared by feed pipe of gaseous HCl tomethanol; determination of the HCl content is made by weight) is addeduntil a pH of 2 is achieved. The resulting yellow solution is stirredfor additional 4 hours, then quenched by addition of 10% aqueous sodiumcarbonate solution to give a pH above 7. After extraction withdichloromethane the combined organic phase are dried over sodiumsulfate, filtered and evaporated to dryness. The resulting yellow oil ispurified by column chromatography to give(3R/S,5S)-5-biphenyl-4-ylmethyl-3-dimethoxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=Me, R9=Me) as a 88:12 mixture ofdiastereomers [ratio of (3S):(3R) diastereomers, respectively]. 1H NMR(CDCl₃): Data for mixture of diastereomers: 1.62, 1.64, 1.89, 2.02,2.26, 2.40, 2.69, 2.81, 2.92, 3.14, 3.20, 3.39, 3.44, 3.47, 3.52, 4.29,4.40, 4.69, 7.27-7.39, 7.46, 7.56-7.62. Ratio of diastereomersdetermined by integration of the pairs of signals at 3.39 ppm and 3.44ppm (major and minor diastereomer, respectively) or 3.47 ppm and 3.52ppm (major and minor diastereomer, respectively).

(3R/S,5S)-5-biphenyl-4-ylmethyl-3-dimethoxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=Me, R9=Me) as a 88:12 mixture ofdiastereomers [ratio of (3S):(3R) diastereomers, respectively] can berecrystallised from tert-butylmethylether to afford(3S,5S)-5-Biphenyl-4-ylmethyl-3-dimethoxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=Me, R9=Me).

The X-ray Structure of the obtained crystals is shown in FIG. 5 a.

Crystal Data [Recorded at 120(2) K]

Empirical formula C₂₅H₃₁NO₅ Formula weight 425.51 Crystal systemOrthorhombic Space group P212121 Cell parameters a = 6.645(2) Å b =15.761(4) Å c = 22.439(6) Å α = 90° β = 90° γ = 90° Volume of unit cell2350.1(11) Å³ Z^(*) 4 Calculated density 1.203 mg m⁻³ ^(*)(number ofasymmetric units in the unit cell)

(3R/S,5S)-5-biphenyl-4-ylmethyl-3-dimethoxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=Me, R9=Me) as a 88:12 mixture ofdiastereomers [ratio of (3S):(3R) diastereomers, respectively] can berecrystallised from ethyl acetate/heptane to afford(3S,5S)-5-Biphenyl-4-ylmethyl-3-dimethoxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=Me, R9=Me).

The X-ray Structure of the obtained crystals is shown in FIG. 5 b.

Crystal Data [Recorded at 100(2) K]

Empirical formula C₂₅H₃₁NO₅ Formula weight 425.51 Crystal systemOrthorhombic Space group P212121 Cell parameters a = 6.638(3) Å b =15.746(6) Å c = 22.420(8) Å α = 90° β = 90° γ = 90° Volume of unit cell2343.4(16) Å³ Z_(*) 4 Calculated density 1.206 mg m⁻³ ^(*)(number ofasymmetric units in the unit cell)

Example 30((3R/S,5S)-5-Biphenyl-4-ylmethyl-1-tert-butoxycarbonyl-2-oxo-pyrrolidin-3-ylmethyl)trimethylammoniumiodide (10-a, R1=Boc, R6=Me, R7=Me, R10=Me)

(3R/S,5S)-biphenyl-4-ylmethyl-3-dimethylaminomethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (9-a, R1=Boc, R6=Me, R7=Me) (108 mg) (ratio ofdiastereomers (3S):(3R), 85:15 according to NMR analysis) is dilutedwith 4 ml methanol and 328 μl methyl iodide is then added. The reactionmixture is then stirred at room temperature for 17 h. The mixture isthen concentrated to dryness to give((3R/S,5S)-5-Biphenyl-4-ylmethyl-1-tert-butoxycarbonyl-2-oxo-pyrrolidin-3-ylmethyl)trimethylammoniumiodide (10-a, R1=Boc, R6=Me, R7=Me, R10=Me). 1H NMR (DMSO): 1.51 (9H),1.98 (1H), 2.18 (1H), 3.00 (1H), 3.08 (1H), 3.13 (9H), 3.38-3.43 (2H),3.72 (1H), 4.25 (1H), 7.38 (1H), 7.42 (2H), 7.48 (2H), 7.67 (4H). m/z:423 ([M]⁺, 100%). IR (solution in CH₂Cl₂, vice): 3040; 1781; 1742; 1724;1487; 1371; 1298; 1277; 1150; 985. On the basis of NMR, the ratio ofdiastereomers (3S):(3R) is 85:15.

Example 31(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a. R1=Boc)

Crude(3R/S,5S)-biphenyl-4-ylmethyl-3-dimethylaminomethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (9-a, R1=Boc, R6=Me, R7=Me) (13.8 g) is dilutedwith 40 ml methanol and 16.9 ml methyl iodide is then added. Thereaction mixture is then stirred at room temperature overnight and issubsequently concentrated to dryness. 30 ml saturated NaHCO₃ solutionand 15 ml dichloromethane are then added to the residue. The resultingemulsion is stirred at room temperature for 10 h. The organic layer isthen separated, washed with water, dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified using columnchromatography (pentane/tert-butyl methyl ether=8:2 to 7:3) to give(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as in Example23.

HPLC Method (Example 31)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

9-b (R1=Boc; R6=Me; R7=Me): 10.5 min 9-c (R1=Boc; R6=Me; R7=Me): 11.0min 4-a (R1=Boc): 12.0 min Example 32(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H)

(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) (27.7 g) is dissolved in THF (270ml) at room temperature. Tetrabutylammonium bromide (0.24 g) is addedfollowed with water (10 ml). The mixture is then cooled to 10° C. Asolution of lithium hydroxide (7.3 g) in water (92 ml) is added over 2h. Phosphoric acid (37 g, 85%) is added until pH 3. Phases are thenseparated. The organic phase is diluted with toluene (100 ml) and washedwith brine. Phases are separated. The organic phase is then concentratedin vacuo. The residue is dissolved in acetonitrile (350 ml) at 80° C.and azeotropically distilled. Further acetonitrile is added (150 ml) andthe mixture cooled to 0° C. The solid is collected by filtration anddried, to afford(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) (25.7 g). δ_(H) (400 MHz, DMSO) 1.30 (9H),2.29 (1H), 2.50 (1H), 2.75 (2H), 3.91 (8H), 5.62 (1H), 6.09 (1H), 6.66(1H), 7.28 (2H), 7.33 (1H), 7.44 (2H), 7.56 (2H), 7.63 (2H).

(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) is a crystalline solid. Reflections in theX-ray diffraction pattern show the following interlattice planeintervals (average 2θ in [°] are indicated with error limit of ±0.2): 2θin [°]: 4.4, 6.2, 8.6, 9.0, 9.9, 12.5, 13.4, 13.8, 14.1, 16.0, 17.8,18.4, 19.3, 20.8, 21.7, 22.2, 23.1, 24.6, 25.0, 25.7, 27.6. The mostintensive reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 4.3, 6.2, 8.6, 9.9, 12.5, 13.4,16.0, 17.8, 18.4, 19.3. Data taken using a Bruker D8 Advancediffractometer using Cu—Kα radiation.

HPLC Method (Example 32)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

2-a (R1=Boc; R2=H; R3=CO₂H): 2.40 min 4-a (R1=Boc): 12.0 min Example 33(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H)

210 g (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) is added to 1285 g (2000 ml) of a mixturecontaining compounds of formula 13, 14, 15 (wherein R6=Me, R7=Me,R8=tBu) at room temperature. The solution is heated to 80-85° C. andstirred for about 15 h. The solution is concentrated under vacuum (90°C., 30 mbar) to yield a residue. (The collected distillate, containingcompounds of formula 13, 14, 15 (wherein R6=Me, R7=Me, R8=tBu), may beoptionally reused in subsequent reactions, where appropriate). Theresidue is dissolved in 1430 ml tetrahydrofuran. 37.8 g sulfuric aciddiluted in 638 ml water is then added. The mixture is subsequentlyvigorously stirred at 10-15° C. During this time, the pH is maintainedin the range pH 2-3 by the addition of further portions of sulfuricacid, as required. After 1 h the lower aqueous phase is removed, and theremaining organic phase washed with about 6 g saturated potassiumcarbonate solution. 1194 g Potassium carbonate solution (1M solution) isthen added, followed by 3.94 g tetra butyl ammonium hydroxide solution(40%) and 133 g aqueous formaldehyde solution (37%). This mixture isheated to 40-45° C. and stirred heavily for about 2 hours. The aqueousphase is then removed. To the remaining organic phase, 300 ml water isadded. 97 g Sodium sulfite solution (40%) is then added whilstmaintaining the temperature below 40° C. Afterwards, the aqueous phaseis removed and is replaced with 600 ml of fresh water. The THF isremoved by distillation (jacket 50° C., 100-200 mbar) to provide a whitesuspension. 1500 ml toluene is added at 50° C. Again the lower aqueousphase is removed and the remaining organic phase is washed with about200 ml water. The latter is partially concentrated under vacuum in orderto remove any water by azeotrope distillation while the distillate isreplaced with fresh toluene. Afterwards, 54 g diazabicycloundecene (DBU)is added as well as 17 g methansulfonylchloride, cautiously at 20-25° C.After one hour stirring, about 300 ml water is added followed by 1.4 gconcentrated sulfuric acid in order to lower the pH to 6-7. The aqueousphase is removed and the remaining organic phase washed with 300 mlwater. 600 ml Water is added and the solvent removed by distillationunder reduced pressure to yield a white suspension. About 1500 ml THF isthen added followed by 57 g lithium hydroxide dissolved in 300 ml water.The mixture is stirred heavily at 10-15° C. for about 2 hours. 100 gPhosphoric acid (58%) is then added cautiously in order to adjust the pHtowards 3-4. About 300 ml toluene is then added, and the aqueous phaseremoved. The remaining organic phase is washed with 200 ml brine andconcentrated to one half the original volume under vacuum. The residueis diluted with 300 ml THF and filtered. The THF is then replaced byacetonitrile by distillation, while maintaining the volume constant bydistillation under vacuum. After removal of the majority of THF, thedesired product crystallizes giving rise to a thick slurry. The later iscooled to 0° C., and the solid recovered by filtration. The later isdried under vacuum at 50° C. to yield(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H). Spectroscopic data as Example 32.

HPLC Method (Example 33)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60±2° C.

Retention times:

2-a (R1=Boc; R2=H; R3=CO₂H): 2.40 min 6-a (R1=Boc): 2.62 min 5-a(R1=Boc): 8.39 min 8-a (R1=Boc): 10.4 min 7-a (R1=Boc; R6=Me; R7=Me):11.0 min 4-a (R1=Boc): 12.0 min Example 34 (3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc)

Method 1

1.3 g(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is dissolved in 40 mlof ethyl acetate. After addition of 0.3 g 10% Pd/C (Engelhard 4505) thesystem is flushed several times with hydrogen and subsequently stirredat 20° C. and 4 bar hydrogen for 5 days. The resulting reaction mixtureis filtered through cellflock and concentrated to dryness yielding(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 33:67 (3-a,R1=Boc: 3-b, R1=Boc) as determined by hplc.

Method 2

(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6,=Me, R7=Me) is added totetrahydrofuran, to achieve a substrate concentration of 0.05 M.Triethylamine (1 equivalent) is added to the mixture. 5% Pd/C A102023(25% w/w) is then added to the mixture. The mixture is then pressurisedunder a hydrogen atmosphere to 20 bar. The mixture is stirred at 40° C.for 3 h. The mixture is then filtered to remove the catalyst andconcentrated under reduced pressure. The diastereomer ratio is 39:61(3-a, R1=Boc: 3-b, R1=Boc) as determined by hplc.

General Procedure (Methods 3-8)

(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added totetrahydrofuran, methanol or isopropyl acetate at ambient temperature,to achieve a substrate concentration of 0.05 M, 0.167 M or 0.25 M. Ahetereogeneous catalyst (25 mas % with respect to 7-a) is then added tothe mixture. The mixture is then pressurised under a hydrogen atmosphereto 20 bar. The mixture is stirred at 40° C., 45° C., 55° C. or 65° C.for 1.5 or 3 h. The mixture is then filtered to remove the catalyst andconcentrated under reduced pressure.

Method 3

Catalyst: 5% Pd(S)/C A103038; Tetrahydrofuran; 0.05 M; 55° C.; 3 h.Diastereomer ratio 29:71 (3-a, R1=Boc: 3-b, R1=Boc) as determined byhplc.

Method 4

Catalyst: 5% Pd/C type 39; Methanol; 0.05 M; 55° C.; 3 h. Diastereomerratio 42:58 (3-a, R1=Boc: 3-b, R1=Boc) as determined by hplc.

Method 5

Catalyst: 5% Pd(S)/C A103038; Tetrahydrofuran; 0.167 M; 40° C.; 1.5 h.Diastereomer ratio 14:86 (3-a, R1=Boc: 3-b, R1=Boc) as determined byhplc.

Method 6

Catalyst: 5% Pd(S)/C A103038; Tetrahydrofuran; 0.167 M; 40° C.; 3 h.Diastereomer ratio 21:79 (3-a, R1=Boc: 3-b, R1=Boc) as determined byhplc.

Method 7

Catalyst: 5% Pd/C type 37; Isopropyl acetate; 0.167 M; 65° C.; 3 h.Diastereomer ratio 34:66 (3-a, R1=Boc: 3-b, R1=Boc) as determined byhplc.

Method 8

Catalyst: 5% Pd/C type 39; Tetrahydrofuran; 0.25 M; 65° C.; 3 h.Diastereomer ratio 39:61 (3-a, R1=Boc: 3-b, R1=Boc) as determined byhplc.

Method 9

1.3 g(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethylacetate (40 ml) at ambient temperature. 0.3 g of 10% Palladium on Carbon(Engelhard 4505) and water (0.3 ml) is added to the mixture. The mixtureis then pressurised under a hydrogen atmosphere to 4 bar. The mixture isstirred at ambient temperature and 4 bar hydrogen pressure for 4 days.The mixture is then filtered to remove the catalyst and concentratedunder reduced pressure. The residue is then purified by columnchromatography (ethyl acetate/hexane, 70:30) to afford(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 67:33 (3-a,R1=Boc: 3-b, R1=Boc) as determined by hplc.

Method 10

1.3 g(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethylacetate (40 ml) at ambient temperature. 0.3 g of Lindlar Catalyst (exAldrich) is added to the mixture. The mixture is then pressurised undera hydrogen atmosphere to 2 bar. The mixture is stirred at ambienttemperature and 2 bar hydrogen pressure for 3 days. The mixture is thenfiltered to remove the catalyst and concentrated under reduced pressure.The residue is then purified by column chromatography (ethylacetate/hexane, 70:30) to afford(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 99.2:0.8 (3-a,R1=Boc: 3-b, R1=Boc) as determined by hplc.

Method 11

1.3 g(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethylacetate (40 ml) at ambient temperature. 0.3 g of 10% Palladium on Carbon(Engelhard 4505) is added to the mixture. The mixture is thenpressurised under a hydrogen atmosphere to 2 bar. The mixture is stirredat ambient temperature and 2 bar hydrogen pressure for 3 days. Themixture is then filtered to remove the catalyst and concentrated underreduced pressure. The residue is then purified by column chromatography(ethyl acetate/hexane, 70:30) to afford(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 88.8:11.2 (3-a,R1=Boc: 3-b, R1=Boc) as determined by hplc.

Method 12

1.3 g(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethylacetate (40 ml) at ambient temperature. 0.3 g of 10% Palladium on Carbon(Engelhard 4505) and one drop of aqueous sodium hydroxide solution areadded to the mixture. The mixture is then pressurised under a hydrogenatmosphere to 4 bar. The mixture is stirred at ambient temperature and 4bar hydrogen pressure for 4 days. The mixture is then filtered to removethe catalyst and concentrated under reduced pressure. The residue isthen purified by column chromatography (ethyl acetate/hexane, 70:30) toafford(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 76:24 (3-a,R1=Boc: 3-b, R1=Boc) as determined by hplc.

HPLC Method 1 (Example 34, Methods 1, 9, 10, 11 and 12)

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 10 min (70% B), 11 min (70% B), 13 min (80% B),16 min (80% B), 16.1 min (20% B), 19 min 20% B). Flow rate: 1.4 ml min¹.Wavelength: 210 or 254 nm. Temperature 55±2° C.

Retention times:

7-a (R1=Boc; R6=Me; R7=Me): 9.6 min 3-a and 3-b (R1=Boc): 10.3 min HPLCMethod 2 (Example 34, Methods 1, 9, 10, 11 and 12)

Column: Chiralpak AD-RH, 150×2.6 mm, 5.0 μm. Mobile Phase A (Water);Mobile

Phase B (Acetonitrile). Isocratic: 0 min (80% B); 15 min (80% B). Flowrate: 0.5 ml min⁻¹. Wavelength: 210 nm.

Retention times:

3-a, R1=Boc: 6.3 min 3-b, R1=Boc: 6.9 min HPLC Method 3 (Example 34,Methods 2-8)

Column: AD-RH Chiralpak; 150×4.6 mm. Mobile Phase A (water); MobilePhase B (Acetonitrile). Isocratic: 0 min (20% B); 15 min (20% B). Flowrate: 0.5 ml Wavelength 210 nm. Column temperature 40° C.

Retention times:

(3-a, R1=Boc): 6.2 min (3-b, R1=Boc): 6.8 min Example 35Tris(dimethylamino)methane (13, R6=Me, R7=Me),Tert-Butoxy-bis(dimethylamino)methane (14, R6=Me, R7=Me, R8=tBu) andN,N-Dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu)

Method 1

A mixture of 1.01 g N,N-dimethylformamide di-tert-butyl acetal (15,R6=Me, R7=Me, R8=tBu) (Aldrich #358800) and 0.73 gtris(dimethylamino)methane (13, R6=Me, R7=Me) (Aldrich, #221058) arestirred at room temperature overnight. The resulting mixture is cooledto room temperature, affording a solution containing 13, 14 and 15(R6=Me, R7=Me, R8=Me) as determined by nmr (spectroscopic data as inExample 14, Method 1).

Method 2

A mixture of 1.01 g N,N-dimethylformamide di-tert-butyl acetal (15,R6=Me, R7=Me, R8=tBu) (Aldrich #358800) and 0.73 gtris(dimethylamino)methane (13, R6=Me, R7=Me) (Aldrich, #221058) areheated at 45° C. for 4 h. The resulting mixture is cooled to roomtemperature, affording a solution containing 13, 14 and 15 (R6=Me,R7=Me, R8=Me) as determined by nmr (spectroscopic data as in Example 14,Method 1).

Method 3

A mixture of 1.01 g N,N-dimethylformamide di-tert-butyl acetal (15,R6=Me, R7=Me, R8=tBu) (Aldrich #358800) and 0.73 gtris(dimethylamino)methane (13, R6=Me, R7=Me) (Aldrich, #221058) areheated at 80° C. for 1 h. The resulting mixture is cooled to roomtemperature, affording a solution containing 13, 14 and 15 (R6=Me,R7=Me, R8=Me) as determined by nmr (spectroscopic data as in Example 14,Method 1).

Example 36 Tris(dimethylamino)methane (13, R6=Me, R7=Me),Tert-pentoxy-bis(dimethylamino)methane (14, R6=Me, R7=Me, R8=CMe₂Et) andN,N-Dimethylformamide di-tert-pentoxyacetal (15, R6=Me, R7=Me,R8=CMe₂Et)

Method 1

57.5 g N,N,N,N-tetramethylformamidinium chloride is added to 93 g sodiumamylate 40% solution in toluene. The resulting mixture is stirred atroom temperature for 48 h. The mixture is then filtered and the cakewashed with toluene (22 g) to afford a solution containing 13, 14 and 15(R6=Me, R7=Me, R8=CMe₂Et). A sample of the filtrate is concentrated invacuo. 1H NMR(C₆D₆): 0.81-0.84, 0.92-0.98, 1.02, 1.10, 1.20, 1.30-1.34,1.47-1.62, 2.29, 2.33, 3.02, 4.06, 5.02. Relative amounts of 13 (R6=Me;R7=Me), 14 (R6=Me, R7=Me, R8=tBu), 15 (R6=Me, R7=Me, R8=Me) aredetermined by integration of signals at 3.02, 4.06 and 5.02 ppm,respectively.

Method 2

41 g N,N,N,N-tetramethylformamidinium chloride is added to 67 g sodiumamylate 40% solution in toluene. The resulting mixture is stirred atroom temperature for 48 h. The mixture is filtered and the cake washedwith toluene (2×10 ml). The mixture is then diluted to a total volume of100 ml to afford a solution containing 13, 14 and 15 (R6=Me, R7=Me,R8=CMe₂Et). Spectroscopic data as for Example 36, Method 1.

Example 37(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid diisopropylethylammonium salt (1-a, R1=Boc, R2=H, R3=CO₂⁻[NHiPr₂Et]⁺)

1 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) is added to ethanol (10 ml).Diisopropylethylamine (0.454 ml) is then added and the mixture isstirred at room temperature for 30 minutes. The mixture is thenconcentrated in vacuo to afford(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid diisopropylethylammonium salt (1-a, R1=Boc, R2=H, R3=CO₂⁻[NHiPr₂Et]⁺). 1H NMR (DMSO-d6): 0.95-0.98 (15H), 1.04 (3H), 1.32 (9H),1.36 (1H), 1.74 (1H), 2.38-2.49 (3H), 2.67 (2H), 2.99 (2H), 3.66 (1H),6.29 and 6.70 (1H), 7.23-7.25 (2H), 7.33-7.37 (1H), 7.42-7.46 (2H),7.55-7.57 (2H), 7.62-7.64 (2H).

Example 38(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid triethylammonium salt (1-a, R1=Boc, R2=H, R3=CO₂ ⁻[NHEt₃]⁺)

1 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) is added to ethanol (10 ml).Triethylamine (0.264 ml) is then added and the mixture is stirred atroom temperature for 30 minutes. The mixture is then concentrated invacuo to afford(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid triethylammonium salt (1-a, R1=Boc, R2=H, R3=CO₂ ⁻[NHEt₃]⁺). 1H NMR(DMSO-d6): 0.95 (9H), 1.04 (3H), 1.32 (9H), 1.36 (1H), 1.74 (1H),2.38-2.50 (7H), 2.67 (2H), 3.65 (1H), 6.29 and 6.70 (1H), 7.23-7.25(2H), 7.33-7.37 (1H), 7.43-7.48 (2H), 7.55-7.57 (2H), 7.62-7.64 (2H).

Example 39(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid sodium salt (1-a, R1=Boc, R2=H, R3=CO₂ ⁻Na⁺)

1 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (R1=Boc, R2=H, R3=CO₂H) is added to ethanol (10 ml). Sodiummethoxide (141 mg) is then added and the mixture is stirred at roomtemperature for 30 minutes. The mixture is then concentrated in vacuo toafford(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid sodium salt (1-a, R1=Boc, R2=H, R3=CO₂ ⁻Na⁺). 1H NMR (DMSO-d6):0.91 (3H), 1.29 (1H), 1.34 (9H), 1.61 (1H), 2.12 (1H), 2.68-2.81 (2H),3.60 (1H), 7.25-7.27 (2H), 7.32-7.36 (1H), 7.43-7.47 (2H), 7.55-7.57(2H), 7.64-7.66 (2H), 7.76 (1H).

Example 40(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H),(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-b, R1=Boc, R2=H, R3=CO₂H),

Method 1

20 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) is added to ethanol (400 μl). 10% Palladiumon carbon (2 mg, 50% water wet, Degussa type E101 NE/W) is then added.Hydrogen gas at ambient pressure is applied to the mixture. The mixtureis stirred at ambient temperature and pressure overnight. The mixture isthen filtered over Celite and washed with ethanol (2×0.5 ml). Themixture is then concentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-b, R1=Boc, R2=H, R3=CO₂H). 1H NMR (CDCl₃): 1.11-1.16, 1.21 and1.33, 1.39-1.53, 1.70-1.92, 2.32-2.81, 3.72-3.97, 4.44-4.50, 6.41 and6.56, 7.16-7.49, 10.84.

Method 2

20 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) is added to isopropyl acetate (400 μl). 10%Palladium on carbon (2 mg, 50% water wet, Degussa type E101 NE/W) isthen added. Hydrogen gas at ambient pressure is applied to the mixture.The mixture is stirred at ambient temperature and pressure overnight.The mixture is then filtered over Celite and washed with isopropylacetate (2×0.5 ml). The mixture is then concentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-b, R1=Boc, R2=H, R3=CO₂H). Spectroscopic data as in Example 40,Method 1.

Method 3

20 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) is added to isopropyl acetate (400 μl). 10%Platinium on carbon (2 mg) is then added. Hydrogen gas at ambientpressure is applied to the mixture. The mixture is stirred at ambienttemperature and pressure overnight. The mixture is then filtered overCelite and washed with isopropyl acetate (2×0.5 ml). The mixture is thenconcentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-b, R1=Boc, R2=H, R3=CO₂H). Spectroscopic data as in Example 40,Method 1.

Method 4

20 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) is added to isopropyl acetate (400 μl). 5%Rhodium on carbon (2 mg) is then added. Hydrogen gas at ambient pressureis applied to the mixture. The mixture is stirred at ambient temperatureand pressure overnight. The mixture is then filtered over Celite andwashed with isopropyl acetate (2×0.5 ml). The mixture is thenconcentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-b, R1=Boc, R2=H, R3=CO₂H). Spectroscopic data as in Example 40,Method 1.

Example 41(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidpotassium salt (2-a, R1=Boc, R2=H, R3=CO₂K)

500 mg(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) is added to ethanol (5 ml) at roomtemperature. 2.6 ml of a 0.5 M Potassium hydroxide in ethanol solutionis added to the mixture over a period of 5 minutes. The resultingmixture is stirred for 1 h at room temperature. The solvent is thenremoved under reduced pressure. Toluene (10 ml) is added to the mixture.The solvent is then removed under reduced pressure to give(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidpotassium salt (2-a, R1=Boc, R2=H, R3=CO₂K). 1H NMR (DMSO): 1.35 (9H),2.24-2.37 (2H), 2.67-2.84 (2H), 3.69-3.80 (1H), 5.04 (1H), 5.79 (1H),7.12-7.17, 7.23-7.35, 7.42-7.46, 7.54-7.57, 7.62-7.67.

Example 42(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-a, R1=Boc, R2=H, R3=CO₂K) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-b, R1=Boc, R2=H, R3=CO₂K)

Method 1

100 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidpotassium salt (2-a, R1=Boc, R2=H, R3=CO₂K) (prepared according toprocedure in Example 42) is added to ethanol (1 ml). 10% Palladium oncarbon (10 mg, 50% water wet, Degussa type E101 NE/W) is then added.Hydrogen gas at ambient pressure is applied to the mixture. The mixtureis stirred at ambient temperature and pressure overnight. The mixture isthen filtered over Celite and washed with ethanol (2×1 ml). The mixtureis then concentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-a, R1=Boc, R2=H, R3=CO₂K) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-b, R1=Boc, R2=H, R3=CO₂K). ¹H NMR (CDCl₃):1.06-1.12, 1.31-1.36, 1.80-0.193, 2.25-2.49, 2.62-2.92, 3.74-4.08, 4.81and 5.27, 6.20 and 6.54, 7.24-7.57.

Method 2

100 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidpotassium salt (2-a, R1=Boc, R2=H, R3=CO₂K) (prepared according toprocedure in Example 42) is added to isopropyl acetate (1 ml). 10%Palladium on carbon (10 mg, 50% water wet, Degussa type E101 NE/W) isthen added. Hydrogen gas at ambient pressure is applied to the mixture.The mixture is stirred at ambient temperature and pressure overnight.The mixture is then filtered over Celite and washed with isopropylacetate (2×1 ml). The mixture is then concentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-a, R1=Boc, R2=H, R3=CO₂K) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-b, R1=Boc, R2=H, R3=CO₂K). Spectroscopic data asin Example 42, Method 1.

Method 3

100 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidpotassium salt (2-a, R1=Boc, R2=H, R3=CO₂K) (prepared according toprocedure in Example 42) is added to isopropyl acetate (1 ml). 10%Platinium on carbon (10 mg) is then added. Hydrogen gas at ambientpressure is applied to the mixture. The mixture is stirred at ambienttemperature and pressure overnight. The mixture is then filtered overCelite and washed with isopropyl acetate (2×1 ml). The mixture is thenconcentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-a, R1=Boc, R2=H, R3=CO₂K) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-b, R1=Boc, R2=H, R3=CO₂K). Spectroscopic data asin Example 42, Method 1.

Method 4

100 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidpotassium salt (2-a, R1=Boc, R2=H, R3=CO₂K) (prepared according toprocedure in Example 42) is added to isopropyl acetate (1 ml). 5%Rhodium on carbon (10 mg) is then added. Hydrogen gas at ambientpressure is applied to the mixture. The mixture is stirred at ambienttemperature and pressure overnight. The mixture is then filtered overCelite and washed with isopropyl acetate (2×1 ml). The mixture is thenconcentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-a, R1=Boc, R2=H, R3=CO₂K) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid potassium salt (1-b, R1=Boc, R2=H, R3=CO₂K). Spectroscopic data asin Example 42, Method 1.

Example 43(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H),(2S,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-b, R1=Boc, R2=H, R3=CO₂H),(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid salt (1-a, R1=Boc, R2=H, R3=CO₂ ⁻) or(2S,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid salt (1-b, R1=Boc, R2=H, R3=CO₂)

General Procedure 1

A mixture of Organometallic Catalyst (C) and(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) is added to the Solvent (S) (volume andidentity of solvent given in the Table of Example 43) to achieve theconcentration of 2-a (R1=Boc, R2=H, R3=CO₂H) given in the Table ofExample 43 and an S/C ratio as given in the Table of Example 43.

Optionally and according to the Table of Example 43, an Additive (D) maybe added at this stage. The identity and amount of the additive is givenin the Table of Example 43. The amount of additive to be used isrelative to the moles of(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) used.

Hydrogen has is then applied to the vessel containing the mixture(temperature, time and pressure are given in the Table of Example 43).

The volatiles are removed under reduced pressure and the resultingresidue analysed by hplc to determine the ratio of (1-a, R1=Boc, R2=H,R3=CO₂H) or (1-a, R1=Boc, R2=H, R3=CO₂ ⁻) to (1-b, R1=Boc, R2=H,R3=CO₂H) or (1-b, R1=Boc, R2=H, R3=CO₂ ⁻).

General Procedure 2

Solvent (S) (volume and identity of solvent given in the Table ofExample 43) is added to a mixture of the Organometallic Complex (A) andthe Chiral Ligand (L). The mixture is stirred for 0.5 h at roomtemperature.(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) in a solvent (volume and identity ofsolvent given in the Table of Example 43) is then added. The finalconcentration of 2-a (R1=Boc, R2=H, R3=CO₂H) is given in the Table ofExample 43. The S/C ratio is given in the Table of Example 43. The ratioof Chiral Ligand per atom of metal within the Organometallic Complex isgiven in the Table of Example 43.

Hydrogen gas is then applied to the vessel containing the mixture(temperature, time and pressure is given in the Table of Example 43).

The volatiles are removed under reduced pressure and the resultingresidue analysed by hplc to determine the ratio of (1-a, R1=Boc, R2=H,R3=CO₂H) or (1-a, R1=Boc, R2=H, R3=CO₂ ⁻) to (1-b, R1=Boc, R2=H,R3=CO₂H) or (1-b, R1=Boc, R2=H, R3=CO₂ ⁻).

General Procedure 3

(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) in a Solvent (S) (0.244 ml, identity ofsolvent given in the Table of Example 43) is added to the vesselcontaining the Organometallic Catalyst (C). Further solvent (identitygiven in the Table of Example 43) is added to give a final concentrationof 2-a ((R1=Boc, R2=H, R3=CO₂H) given in the Table of Example 43. TheS/C ratio is given in the Table of Example 43.

Optionally and according to the Table of Example 43, an Additive (D) maybe added at this stage. The identity and amount of the additive is givenin the Table of Example 43. The amount of additive to be used isrelative to the moles of(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) used.

The mixture is then stirred at the temperature and pressure given in theTable of Example 43 for a period of time also indicated in the Table ofExample 43.

The crude reaction solutions are analysed by hplc to determine the ratioof (1-a, R1=Boc, R2=H, R3=CO₂H) or (1-a, R1=Boc, R2=H, R3=CO₂ ⁻) to(1-b, R1=Boc, R2=H, R3=CO₂H) or (1-b, R1=Boc, R2=H, R3=CO₂ ⁻).

General Procedure 4

The Organometallic Complex (A) and Chiral Ligand (L) are added to amixture of ethanol (0.041 ml) and dichloroethane (0.135 ml). The mixtureis stirred for 0.5 h. The solvent is then removed under reducedpressure.(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) in a Solvent (S) (0.244 ml, identity ofsolvent given in the Table of Example 43) is added to the vesselcontaining the Organometallic Complex (A) and Chiral Ligand (L). Furthersolvent (identity given in the Table of Example 43) is added to give thefinal concentration of 2-a (R1=Boc, R2=H, R3=CO₂H) shown in the Table ofExample 43. The S/C ratio is given in the Table of Example 43. The ratioof Chiral Ligand per atom of metal within the Organometallic Complex isgiven in the Table of Example 43.

Optionally and according to the Table of Example 43, an Additive (D) maybe added at this stage. The identity and amount of the additive is givenin the Table of Example 43. The amount of additive to be used isrelative to the moles of(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) used.

Hydrogen gas is the applied to the vessel containing the mixture(temperature, time and pressure is given in the Table of Example 43).

The crude reaction solutions are analysed by hplc to determine the ratioof (1-a, R1=Boc, R2=H, R3=CO₂H) or (1-a, R1=Boc, R2=H, R3=CO₂ ⁻) to(1-b, R1=Boc, R2=H, R3=CO₂H) or (1-b, R1=Boc, R2=H, R3=CO₂ ⁻).

General Procedure 5

Solvent (S) (volume and identity of solvent given in the Table ofExample 43) is added to a mixture of the Organometallic Complex (A) andthe Chiral Ligand (L) in Vessel A. The mixture is stirred for 15 min atroom temperature.

Solvent (S) (volume and identity of solvent given in the Table ofExample 43) is added to(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) in Vessel B.

The contents of Vessel A and Vessel B are transferred to Vessel C(empty). The final concentration of 2-a (R1=Boc, R2=H, R3=CO₂H) is givenin the Table of Example 43. The S/C ratio is given in the Table ofExample 43. The ratio of Chiral Ligand per atom of metal within theOrganometallic Complex is given in the Table of Example 43.

Hydrogen gas is then applied to Vessel C (temperature, time and pressureis given in the Table of Example 43).

The crude reaction solutions are analysed by hplc to determine the ratioof (1-a, R1=Boc, R2=H, R3=CO₂H) or (1-a, R1=Boc, R2=H, R3=CO₂) to (1-b,R1=Boc, R2=H, R3=CO₂H) or (1-b, R1=Boc, R2=H, R3=CO₂).

General Procedure 6

Solvent (S) (volume and identity of solvent given in the Table ofExample 43) is added to a mixture of the Organometallic Complex (A) andthe Chiral Ligand (L) in Vessel A. The mixture is stirred for 0.5 h atroom temperature.

The mixture is transferred to Vessel B containing(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) and optionally (as indicated in the Tableof Example 43),4-diazobicyclo[2.2.2]octane (amount given in the Table ofExample 43). The amount of 1,4-diazobicyclo[2.2.2]octane used isrelative to the moles of(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) used. The final concentration of 2-a(R1=Boc, R2=H, R3=CO₂H) is given in the Table of Example 43. The S/Cratio is given in the Table of Example 43. The ratio of Chiral Ligandper atom of metal within the Organometallic Complex is given in theTable of Example 43.

Optionally and according to the Table of Example 43, methanesulphonicacid may be added at this stage to Vessel B. The amount ofmethanesulphonic acid used is relative to the moles of(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) used and is given in the Table of Example43.

Hydrogen gas is then applied to Vessel B and its contents at thetemperature, time and pressure given in the Table of Example 43.

The crude reaction solutions are analysed by hplc to determine the ratioof (1-a, R1=Boc, R2=H, R3=CO₂H) or (1-a, R1=Boc, R2=H, R3=CO₂ ⁻) to(1-b, R1=Boc, R2=H, R3=CO₂H) or (1-b, R1=Boc, R2=H, R3=CO₂).

General Procedure 7

Solvent (S) (volume and identity of solvent as given in the Table ofExample 43) is added to a mixture of the Organometallic Complex (A) andthe Chiral Ligand (L) in Vessel A. Hydrogen gas (1 bar) is applied toVessel A and the mixture stirred for 5 min at ambient temperature.

Solvent (volume and identity of solvent given in the Table of Example43) is added to(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) in Vessel B.

The contents of Vessel A and Vessel B are transferred to Vessel C(empty). The final concentration of 2-a (R1=Boc, R2=H, R3=CO₂H) is givenin the Table of Example 43. The S/C ratio is given in the Table ofExample 43. The ratio of Chiral Ligand per atom of metal within theOrganometallic Complex is given in the Table of Example 43.

Hydrogen gas is then applied to Vessel C and its contents (temperature,time and pressure is given in the Table of Example 43.

The crude reaction solutions are analysed by hplc to determine the ratioof (1-a, R1=Boc, R2=H, R3=CO₂H) or (1-a, R1=Boc, R2=H, R3=CO₂ ⁻) to(1-b, R1=Boc, R2=H, R3=CO₂H) or (1-b, R1=Boc, R2=H, R3=CO₂ ⁻).

General Procedure 8

Solvent (S) (volume and identity of solvent given in the Table ofExample 43) is added to a mixture of the Organometallic Complex (A) andthe Chiral Ligand (L) in Vessel A. The mixture is stirred for 15 min atroom temperature.

Solvent (volume and identity of solvent given in the Table of Example43) is added to(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂H) in Vessel B. The mixture is heated at 70°C. for 0.5 h

The contents of Vessel A and Vessel B are transferred to Vessel C(empty). The final concentration of 2-a (R1=Boc, R2=H, R3=CO₂H) is givenin the Table of Example 43. The S/C ratio is given in the Table ofExample 43. The ratio of Chiral Ligand per atom of metal within theOrganometallic Complex is given in the Table of Example 43.

Hydrogen gas is then applied to Vessel C (temperature, time and pressureis given in the Table of Example 43.

The crude reaction solutions are analysed by hplc to determine the ratioof (1-a, R1=Boc, R2=H, R3=CO₂H) or (1-a, R1=Boc, R2=H, R3=CO₂ ⁻) to(1-b, R1=Boc, R2=H, R3=CO₂H) or (1-b, R1=Boc, R2=H, R3=CO₂ ⁻).

HPLC Method 1 (Reactions performed according to Example 43, GeneralProcedures 1 or 2).

Column: Chiralpak QD-AX; 150×4.6 mm; 5 μm. Mobile Phase A: Methanol,0.05% AcOH (v/v), 0.01% NH₄OAc (m/v). Isocratic: 0 min (100% A); 15 min(100% A). Flow rate 0.8 ml Wavelength: 254 nm. Column temperature:ambient (20-25° C.).

Retention times:

(1-a, R1=Boc, R2=H, R3=CO₂H): 8.3 min (1-b, R1=Boc, R2=H, R3=CO₂H): 5.0min (2-a, R1=Boc, R2=H, R3=CO₂H): 5.7 min

HPLC Method 2 (Reactions performed according to Example 43, GeneralProcedures 3, 4, 5, 6, 7, or 8).

Column: Chiralpak QD-AX; 150×4.6 mm; 5 μm. Mobile Phase A: Methanol,0.05% AcOH (v/v), 0.01% NH₄OAc (m/v). Isocratic: 0 min (100% A); 20 min(100% A). Flow rate: 0.8 ml min⁻¹. Wavelength: 220 nm. Columntemperature: 25° C.

Retention times:

(1-a, R1=Boc, R2=H, R3=CO₂H): 5.0 min (1-b, R1=Boc, R2=H, R3=CO₂H): 5.8min (2-a, R1=Boc, R2=H, R3=CO₂H): 8.4 min Case 52466A

Table of Example 43: Ratio of Ligand Ratio 2-a (R1 = Boc, Amount of 2-aSolvent Transition Metal Catalyst per atom of R2 = H, R3 = CO₂H) (R1 =Boc, Volume Organometallic Chiral metal within the to Transition MetalR2 = H, (2-a, R1 = Boc, General Catalyst Organometallic LigandOrganometallic Catalyst R3 = CO₂H) Solvent R2 = H, R3 = Method Procedure(C) Complex (A) (L) Complex (S/C ratio) (mmol) (S) CO₂H) (ml) 1 4 — A-2L-15 1.20 25 0.042 S-3 — 2 3 C-1 — — — 25 0.042 S-5 — 3 1 C-65 — — — 1000.3 S-1 — 4 3 C-1 — — — 25 0.042 S-1 — 5 6 — A-2 L-48 1.05 500 0.66 S-120 6 4 — A-5 L-36 1.20 100 0.042 S-1 — 7 4 — A-4 L-2 1.20 25 0.042 S-1 —8 1 C-27 — — — 1000 0.6 S-1 — 9 4 — A-2 L-25 1.20 25 0.042 S-1 — 10 1C-48 — — — 100 0.3 S-1 — 11 6 — A-2 L-48 1.05 2500 1.31 S-1 0 12 1 C-27— — — 100 0.3 S-1 — 13 1 C-5 — — — 100 0.3 S-1 — 14 5 — A-2 L-28 1.052500 2.62 S-1 16 15 4 — A-1 L-16 1.20 25 0.042 S-1 — 16 4 — A-2 L-291.20 25 0.042 S-5 — 17 1 C-27 — — — 1000 0.6 S-1 — 18 1 C-27 — — — 10000.6 S-1 — 19 4 — A-5 L-48 1.20 25 0.042 S-1 — 20 1 C-27 — — — 100 0.3S-1 — 21 4 — A-3 L-12 1.20 25 0.042 S-1 — 22 1 C-41 — — — 100 0.3 S-1 —23 4 — A-5 L-17 1.20 25 0.042 S-1 — 24 1 C-17 — — — 100 0.3 S-1 — 25 4 —A-2 L-27 1.20 25 0.042 S-1 — 26 4 — A-5 L-14 1.20 25 0.042 S-1 — 27 1C-38 — — — 100 0.3 S-1 — 28 4 — A-2 L-42 1.20 25 0.042 S-1 — 29 1 C-27 —— — 2500 0.79 S-8 — 30 3 C-3 — — — 25 0.042 S-1 — 31 1 C-19 — — — 1000.3 S-1 — 32 4 — A-5 L-12 1.20 25 0.042 S-1 — 33 4 — A-2 L-21 1.20 250.042 S-1 — 34 5 — A-5 L-36 1.05 2500 1.31 S-1 8 35 1 C-24 — — — 100 0.3S-1 — 36 4 — A-1 L-51 1.20 25 0.042 S-1 — 37 1 C-20 — — — 100 0.3 S-1 —38 1 C-27 — — — 1000 0.6 S-1 — 39 1 C-10 — — — 100 0.3 S-1 — 40 4 — A-2L-11 1.20 25 0.042 S-1 — 41 4 — A-2 L-26 1.20 25 0.042 S-1 — 42 2 — A-7L-106 1.13 100 0.3 S-1 2 43 4 — A-2 L-6 1.20 25 0.042 S-1 — 44 4 — A-2L-1 1.20 25 0.042 S-1 — 45 4 — A-5 L-11 1.20 25 0.042 S-1 — 46 1 C-39 —— — 100 0.3 S-1 — 47 1 C-27 — — — 1000 0.79 S-1 — 48 6 — A-2 L-48 1.05500 0.66 S-2 0 49 1 C-27 — — — 500 0.79 S-9 — 50 3 C-1 — — — 25 0.042S-2 — 51 4 — A-2 L-10 1.20 25 0.042 S-1 — 52 4 — A-5 L-6 1.20 25 0.042S-6 — 53 5 — A-2 L-48 1.05 5000 2.62 S-1 16 54 5 — A-5 L-36 1.05 1001.31 S-1 8 55 4 — A-2 L-3 1.20 25 0.042 S-1 — 56 6 — A-5 L-33 1.05 250.5 S-1 0 57 4 — A-4 L-48 1.20 25 0.042 S-1 — 58 6 — A-2 L-48 1.05 5000.66 S-8 0 59 4 — A-2 L-27 1.20 25 0.042 S-1 — 60 4 — A-2 L-12 1.20 250.042 S-1 — 61 4 — A-2 L-16 1.20 25 0.042 S-3 — 62 1 C-64 — — — 100 0.3S-1 — 63 1 C-27 — — — 2500 0.79 S-1 — 64 6 — A-2 L-48 1.10 500 2.62 S-10 65 5 — A-2 L-48 1.05 2500 2.62 S-1 16 66 1 C-44 — — — 100 0.3 S-1 — 674 — A-2 L-17 1.20 25 0.042 S-1 — 68 5 — A-2 L-48 1.05 2500 2.62 S-1 1669 1 C-27 — — — 2500 0.79 S-8 — 70 1 C-43 — — — 500 0.3 S-1 — 71 4 — A-5L-21 1.20 25 0.042 S-1 — 72 4 — A-2 L-50 1.20 25 0.042 S-5 — 73 1 C-13 —— — 100 0.3 S-9 — 74 1 C-44 — — — 100 0.3 S-1 — 75 5 — A-2 L-48 1.105000 21 S-1 75 76 1 C-40 — — — 1000 0.6 S-1 — 77 6 — A-2 L-48 1.05 5000.66 S-1 0 78 6 — A-2 L-48 1.05 500 1.31 S-1 0 79 5 — A-2 L-28 1.05 25002.62 5-1 16 80 4 — A-4 L-19 1.20 25 0.042 S-1 — 81 4 — A-5 L-30 1.20 250.042 S-1 — 82 1 C-7 — — — 100 0.3 S-9 — 83 4 — A-4 L-25 1.20 25 0.042S-1 — 84 1 — A-6 — — 100 0.3 S-9 — 85 3 C-1 — — — 100 0.042 S-1 — 86 4 —A-2 L-16 1.20 25 0.042 S-1 — 87 1 C-14 — — — 100 0.3 S-1 — 88 5 — A-2L-48 1.05 2500 2.62 S-1 16 89 6 — A-2 L-48 1.10 500 2.62 S-1 0 90 1 C-27— — — 2500 2.1 S-1 — 91 1 C-65 — — — 100 0.3 S-1 — 92 4 — A-2 L-29 1.2025 0.042 S-3 — 93 1 C-37 — — — 100 0.3 S-1 — 94 4 — A-3 L-42 1.20 250.042 S-1 — 95 1 C-28 — — — 100 0.3 S-1 — 96 4 — A-3 L-32 1.20 25 0.042S-1 — 97 1 C-27 — — — 1000 0.79 S-8 — 98 4 — A-2 L-51 1.20 25 0.042 S-1— 99 1 C-7 — — — 100 0.3 S-1 — 100 1 C-7 — — — 100 0.3 S-9 — 101 3 C-2 —— — 25 0.042 S-3 — 102 1 C-27 — — — 1000 0.79 S-10 — 103 5 — A-2 L-481.05 100 1.31 S-1 8 104 4 — A-1 L-27 1.20 25 0.042 S-1 — 105 4 — A-5L-36 1.20 25 0.042 S-3 — 106 4 — A-5 L-43 1.20 25 0.042 S-1 — 107 1 C-43— — — 100 0.3 S-1 — 108 4 — A-2 L-5 1.20 25 0.042 S-1 — 109 4 — A-3 L-311.20 25 0.042 S-1 — 110 1 C-45 — — — 100 0.3 S-9 — 111 4 — A-5 L-42 1.2025 0.042 S-1 — 112 4 — A-2 L-52 1.20 25 0.042 S-1 — 113 5 — A-2 L-481.10 5000 21 S-1 100 114 4 — A-4 L-1 1.20 25 0.042 S-1 — 115 4 — A-2L-36 1.20 25 0.042 S-1 — 116 1 C-18 — — — 100 0.3 S-1 — 117 4 — A-2 L-221.20 25 0.042 S-4 — 118 4 — A-4 L-42 1.20 25 0.042 S-1 — 119 3 C-2 — — —25 0.042 S-2 — 120 3 C-4 — — — 25 0.042 S-1 — 121 1 C-8 — — — 100 0.3S-1 — 122 4 — A-5 L-24 1.20 25 0.042 S-1 — 123 1 C-56 — — — 100 0.3 S-1— 124 1 C-41 — — — 100 0.3 S-1 — 125 4 — A-2 L-31 1.20 25 0.042 S-1 —126 4 — A-5 L-3 1.20 25 0.042 S-1 — 127 4 — A-2 L-37 1.20 25 0.042 S-1 —128 1 C-27 — — — 2500 0.79 S-1 — 129 4 — A-2 L-16 1.20 25 0.042 S-2 —130 6 — A-2 L-28 1.05 500 0.66 S-1 0 131 1 C-42 — — — 100 0.3 S-1 — 1324 — A-5 L-6 1.20 100 0.042 S-1 — 133 1 C-21 — — — 100 0.3 S-1 — 134 5 —A-2 L-48 1.10 2500 21 5-1 60 135 4 — A-3 L-19 1.20 25 0.042 S-1 — 136 4— A-5 L-6 1.20 25 0.042 S-2 — 137 4 — A-5 L-48 1.20 25 0.042 S-1 — 138 1C-40 — — — 100 0.3 S-1 — 139 3 C-2 — — — 25 0.042 S-6 — 140 4 — A-2 L-181.20 25 0.042 S-1 — 141 4 — A-1 L-12 1.20 25 0.042 S-1 — 142 4 — A-2L-22 1.20 25 0.042 S-3 — 143 1 C-27 — — — 2500 2.1 S-8 — 144 1 C-56 — —— 100 0.3 S-1 — 145 1 C-27 — — — 500 0.79 S-10 — 146 4 — A-5 L-49 1.2025 0.042 S-1 — 147 3 C-2 — — — 25 0.042 S-1 — 148 4 — A-5 L-35 1.20 250.042 S-1 — 149 1 C-12 — — — 100 0.3 S-1 — 150 1 C-55 — — — 100 0.3 S-1— 151 3 C-2 — — — 25 0.042 S-7 — 152 1 C-50 — — — 100 0.3 S-1 — 153 1C-49 — — — 100 0.3 S-1 — 154 1 C-47 — — — 100 0.3 S-1 — 155 4 — A-2 L-481.20 25 0.042 S-1 — 156 4 — A-4 L-5 1.20 25 0.042 S-1 — 157 1 C-18 — — —100 0.3 S-10 — 158 1 C-7 — — — 100 0.3 S-1 — 159 4 — A-3 L-17 1.20 250.042 S-1 — 160 1 C-6 — — — 100 0.3 S-1 — 161 1 C-15 — — — 100 0.3 S-1 —162 5 — A-2 L-48 1.05 500 1.31 S-1 8 163 5 — A-2 L-48 1.10 2500 21 S-170 164 5 — A-2 L-48 1.10 2500 11.8 S-1 60 165 4 — A-5 L-34 1.20 25 0.042S-1 — 166 1 C-27 — — — 1000 0.79 S-1 — 167 4 — A-2 L-48 1.20 100 0.042S-1 — 168 1 C-33 — — — 100 0.3 S-1 — 169 1 C-27 — — — 2500 0.79 S-1 —170 3 C-4 — — — 25 0.042 S-1 — 171 1 C-43 — — — 100 0.3 S-1 — 172 1 C-7— — — 100 0.3 S-11 — 173 4 — A-5 L-18 1.20 25 0.042 S-1 — 174 4 — A-2L-32 1.20 25 0.042 S-1 — 175 5 — A-2 L-48 1.05 5000 2.62 S-1 16 176 1C-25 — — — 100 0.3 S-1 — 177 4 — A-5 L-9 1.20 25 0.042 S-1 — 178 4 — A-4L-12 1.20 25 0.042 S-1 — 179 3 C-1 — — — 25 0.042 S-7 — 180 1 C-27 — — —500 0.3 S-1 — 181 5 — A-2 L-28 1.05 500 1.31 S-1 8 182 4 — A-5 L-26 1.2025 0.042 S-1 — 183 1 C-25 — — — 100 0.3 S-1 — 184 1 C-27 — — — 1000 0.79S-9 — 185 1 C-40 — — — 1000 0.6 S-1 — 186 1 C-23 — — — 100 0.3 S-1 — 1875 — A-2 L-48 1.05 100 1.31 S-1 8 188 6 — A-2 L-48 1.05 2500 1.31 S-13 0189 1 C-18 — — — 100 0.3 S-10 — 190 1 C-40 — — — 500 0.3 S-2 — 191 1C-63 — — — 100 0.3 S-1 — 192 5 — A-5 L-36 1.05 500 1.31 S-1 8 193 1 C-43— — — 100 0.3 S-1 — 194 5 — A-2 L-28 1.05 100 1.31 S-1 8 195 1 C-7 — — —100 0.3 S-11 — 196 1 C-27 — — — 1000 0.6 S-1 — 197 1 C-27 — — — 10000.79 S-8 — 198 4 — A-2 L-44 1.20 25 0.042 S-1 — 199 4 — A-4 L-15 1.20 250.042 S-1 — 200 4 — A-2 L-34 1.20 25 0.042 S-1 — 201 5 — A-5 L-36 1.05100 1.31 S-1 8 202 1 C-40 — — — 1000 0.6 S-1 — 203 5 — A-2 L-28 1.052500 2.62 S-1 8 204 1 C-7 — — — 100 0.3 S-10 — 205 1 C-45 — — — 100 0.3S-1 — 206 4 — A-2 L-16 1.20 25 0.042 S-4 — 207 4 — A-2 L-13 1.20 250.042 S-1 — 208 1 C-43 — — — 100 0.3 S-1 — 209 4 — A-5 L-13 1.20 250.042 S-1 — 210 4 — A-5 L-45 1.20 25 0.042 S-1 — 211 4 — A-3 L-25 1.2025 0.042 S-1 — 212 2 — A-7 L-54 1.13 100 0.3 S-1 2 213 5 — A-2 L-48 1.052500 2.62 S-1 16 214 2 — A-7 L-56 1.13 100 0.3 S-1 2 215 4 — A-2 L-221.20 25 0.042 S-2 — 216 1 C-29 — — — 100 0.3 S-1 — 217 4 — A-2 L-29 1.2025 0.042 S-1 — 218 1 C-27 — — — 2500 0.79 S-1 — 219 4 — A-2 L-50 1.20 250.042 S-6 — 220 1 C-18 — — — 100 0.3 S-11 — 221 4 — A-2 L-22 1.20 250.042 S-1 — 222 4 — A-2 L-4 1.20 25 0.042 S-1 — 223 1 C-27 — — — 500 0.3S-8 — 224 4 — A-2 L-15 1.20 100 0.042 S-1 — 225 4 — A-5 L-7 1.20 250.042 S-1 — 226 4 — A-2 L-48 1.20 25 0.042 S-1 — 227 1 C-18 — — — 1000.3 S-9 — 228 1 C-40 — — — 1000 0.6 S-1 — 229 2 — A-7 L-105 1.13 100 0.3S-1 2 230 1 C-25 — — — 500 0.3 S-8 — 231 4 — A-5 L-36 1.20 25 0.042 S-2— 232 5 — A-2 L-48 1.10 2500 2.62 S-1 16 233 4 — A-4 L-17 1.20 25 0.042S-1 — 234 4 — A-5 L-6 1.20 25 0.042 S-1 — 235 1 C-7 — — — 100 0.3 S-10 —236 4 — A-2 L-39 1.20 25 0.042 S-1 — 237 4 — A-5 L-27 1.20 25 0.042 S-1— 238 1 C-9 — — — 100 0.3 S-1 — 239 4 — A-2 L-39 1.20 25 0.042 S-5 — 2401 C-41 — — — 100 0.3 S-1 — 241 5 — A-2 L-48 1.05 100 1.31 S-1 8 242 5 —A-2 L-48 1.05 2500 2.62 S-1 17 243 4 — A-5 L-7 1.20 25 0.042 S-3 — 244 1C-52 — — — 100 0.3 S-1 — 245 4 — A-5 L-36 1.20 25 0.042 S-1 — 246 5 —A-5 L-36 1.05 2500 1.31 S-1 8 247 4 — A-2 L-43 1.20 25 0.042 S-1 — 248 4— A-5 L-23 1.20 25 0.042 S-1 — 249 4 — A-3 L-1 1.20 25 0.042 S-1 — 250 4— A-5 L-33 1.20 25 0.042 S-1 — 251 4 — A-2 L-15 1.20 25 0.042 S-2 — 2526 — A-2 L-48 1.05 25 0.5 S-1 0 253 2 — A-7 L-59 1.13 100 0.3 S-1 2 254 1C-42 — — — 100 0.3 S-1 — 255 1 C-18 — — — 100 0.3 S-9 — 256 1 C-9 — — —100 0.3 S-1 — 257 4 — A-2 L-24 1.20 25 0.042 S-1 — 258 5 — A-2 L-48 1.052500 2.62 S-1 16 259 4 — A-3 L-33 1.20 25 0.042 S-1 — 260 4 — A-2 L-531.20 25 0.042 S-1 — 261 1 C-43 — — — 1000 0.6 S-1 — 262 1 C-27 — — —2500 0.79 S-8 — 263 4 — A-1 L-50 1.20 25 0.042 S-1 — 264 4 — A-2 L-291.20 25 0.042 S-2 — 265 1 C-55 — — — 100 0.3 S-1 — 266 6 — A-5 L-36 1.10100 1.31 S-1 0 267 4 — A-3 L-2 1.20 25 0.042 S-1 — 268 3 C-2 — — — 1000.042 S-1 — 269 1 C-54 — — — 100 0.3 S-1 — 270 4 — A-2 L-50 1.20 250.042 S-1 — 271 1 C-22 — — — 100 0.3 S-1 — 272 4 — A-5 L-47 1.20 250.042 S-1 — 273 1 C-66 — — — 100 0.3 S-1 — 274 1 C-27 — — — 2500 0.79S-8 — 275 1 C-25 — — — 1000 0.6 S-1 — 276 1 C-57 — — — 100 0.3 S-1 — 2771 C-31 — — — 100 0.3 S-1 — 278 1 C-40 — — — 500 0.3 S-1 — 279 5 — A-2L-28 1.05 500 1.31 S-1 8 280 6 — A-2 L-48 1.05 100 1.31 S-1 0 281 5 —A-2 L-48 1.10 2500 11.8 S-1 60 282 4 — A-2 L-50 1.20 25 0.042 S-2 — 2831 C-32 — — — 100 0.3 S-1 — 284 4 — A-2 L-36 1.20 25 0.042 S-1 — 285 1C-43 — — — 500 0.3 S-2 — 286 4 — A-5 L-19 1.20 25 0.042 S-1 — 287 1 C-27— — — 2500 0.79 S-1 — 288 1 C-36 — — — 100 0.3 S-1 — 289 1 C-27 — — —1000 0.79 S-8 — 290 3 C-1 — — — 25 0.042 S-3 — 291 4 — A-2 L-46 1.20 250.042 S-1 — 292 1 C-27 — — — 1000 0.6 S-1 — 293 1 C-27 — — — 1000 0.6S-1 — 294 1 C-30 — — — 100 0.3 S-1 — 295 1 C-55 — — — 100 0.3 S-9 — 2961 C-40 — — — 1000 0.6 S-1 — 297 1 C-53 — — — 100 0.3 S-1 — 298 1 C-27 —— — 1000 0.6 S-1 — 299 4 — A-2 L-48 1.20 25 0.042 S-2 — 300 1 C-48 — — —100 0.3 S-1 — 301 1 C-27 — — — 1000 0.79 S-1 — 302 4 — A-2 L-49 1.20 250.042 S-1 — 303 4 — A-5 L-31 1.20 25 0.042 S-1 — 304 1 C-25 — — — 5000.3 S-1 — 305 1 C-57 — — — 100 0.3 S-1 — 306 1 C-46 — — — 100 0.3 S-1 —307 1 C-27 — — — 1000 0.6 S-1 — 308 4 — A-2 L-15 1.20 25 0.042 S-1 — 3091 C-27 — — — 500 0.3 S-2 — 310 2 — A-7 L-55 1.13 100 0.3 S-1 2 311 1C-25 — — — 100 0.3 S-1 — 312 1 C-45 — — — 100 0.3 S-1 — 313 4 — A-5 L-91.20 25 0.042 S-3 — 314 1 C-64 — — — 100 0.3 S-1 — 315 4 — A-2 L-20 1.2025 0.042 S-1 — 316 5 — A-2 L-48 1.10 100 2.62 S-1 140 317 1 C-54 — — —100 0.3 S-9 — 318 4 — A-5 L-2 1.20 25 0.042 S-1 — 319 1 C-30 — — — 1000.3 S-1 — 320 1 C-50 — — — 100 0.3 S-9 — 321 4 — A-2 L-30 1.20 25 0.042S-1 — 322 1 C-20 — — — 100 0.3 S-1 — 323 6 — A-2 L-48 1.10 2500 1.31 S-10 324 4 — A-5 L-29 1.20 25 0.042 S-1 — 325 4 — A-5 L-5 1.20 25 0.042 S-1— 326 1 C-58 — — — 100 0.3 S-1 — 327 1 C-26 — — — 100 0.3 S-1 — 328 4 —A-2 L-50 1.20 25 0.042 S-3 — 329 5 — A-2 L-48 1.05 100 1.31 S-1 8 330 1C-41 — — — 100 0.3 S-1 — 331 1 C-27 — — — 1000 0.79 S-1 — 332 1 C-21 — —— 100 0.3 S-1 — 333 1 C-62 — — — 100 0.3 S-1 — 334 1 C-13 — — — 100 0.3S-1 — 335 5 — A-2 L-28 1.05 500 1.31 S-1 8 336 1 C-40 — — — 1000 0.6 S-1— 337 1 C-27 — — — 1000 0.79 S-1 — 338 1 C-34 — — — 100 0.3 S-1 — 339 1— A-6 — — 100 0.3 S-1 — 340 1 C-43 — — — 500 0.3 S-8 — 341 1 C-27 — — —1000 0.6 S-1 — 342 4 — A-3 L-15 1.20 25 0.042 S-1 — 343 4 — A-2 L-331.20 25 0.042 S-1 — 344 5 — A-2 L-48 1.05 500 1.31 S-1 8 345 1 C-27 — —— 100 0.3 S-1 — 346 4 — A-5 L-12 1.20 25 0.042 S-1 — 347 1 C-31 — — —100 0.3 S-1 — 348 5 — A-2 L-48 1.05 2500 2.62 S-1 16 349 4 — A-3 L-51.20 25 0.042 S-1 — 350 1 C-60 — — — 100 0.3 S-1 — 351 1 C-27 — — — 10002.1 S-8 — 352 1 C-35 — — — 100 0.3 S-1 — 353 4 — A-5 L-37 1.20 25 0.042S-1 — 354 4 — A-5 L-11 1.20 25 0.042 S-1 — 355 4 — A-5 L-1 1.20 25 0.042S-1 — 356 4 — A-2 L-14 1.20 25 0.042 S-1 — 357 4 — A-2 L-19 1.20 250.042 S-1 — 358 1 C-51 — — — 100 0.3 S-1 — 359 5 — A-2 L-48 1.10 5000 21S-1 100 360 4 — A-5 L-8 1.20 25 0.042 S-1 — 361 4 — A-5 L-44 1.20 250.042 S-1 — 362 4 — A-2 L-6 1.20 25 0.042 S-3 — 363 4 — A-2 L-35 1.20 250.042 S-1 — 364 4 — A-5 L-6 1.20 25 0.042 S-1 — 365 1 C-61 — — — 100 0.3S-1 — 366 5 — A-2 L-48 1.10 100 1.31 S-1 100 367 5 — A-2 L-48 1.05 1001.31 S-1 8 368 1 C-40 — — — 500 0.3 S-8 — 369 1 C-25 — — — 500 0.3 S-2 —370 1 C-18 — — — 100 0.3 S-11 — 371 4 — A-2 L-6 1.20 25 0.042 S-1 — 3721 C-47 — — — 100 0.3 S-1 — 373 6 — A-2 L-48 1.05 2500 1.31 S-13 0 374 4— A-2 L-15 1.20 25 0.042 S-1 — 375 4 — A-5 L-4 1.20 25 0.042 S-1 — 376 1C-27 — — — 1000 0.6 S-1 — 377 4 — A-5 L-36 1.20 25 0.042 S-1 — 378 4 —A-1 L-53 1.20 25 0.042 S-1 — 379 1 C-11 — — — 100 0.3 S-1 — 380 3 C-3 —— — 25 0.042 S-1 — 381 5 — A-2 L-48 1.05 5000 2.62 S-1 16 382 4 — A-2L-23 1.20 25 0.042 S-1 — 383 1 C-59 — — — 100 0.3 S-1 — 384 4 — A-4 L-271.20 25 0.042 S-1 — 385 4 — A-2 L-11 1.20 25 0.042 S-1 — 386 4 — A-2L-22 1.20 25 0.042 S-3 — 387 3 C-4 — — — 25 0.042 S-1 — 388 1 C-44 — — —100 0.3 S-9 — 389 4 — A-3 L-27 1.20 25 0.042 S-1 — 390 7 — A-2 L-48 1.05100 1.31 S-1 12 391 4 — A-3 L-48 1.20 25 0.042 S-1 — 392 4 — A-2 L-451.20 25 0.042 S-1 — 393 4 — A-2 L-2 1.20 25 0.042 S-1 — 394 4 — A-5 L-251.20 25 0.042 S-1 — 395 6 — A-2 L-48 1.05 500 0.66 S-1 0 396 3 C-3 — — —25 0.042 S-1 — 397 4 — A-4 L-33 1.20 25 0.042 S-1 — 398 4 — A-2 L-151.20 25 0.042 S-3 — 399 1 C-27 — — — 100 0.3 S-1 — 400 1 C-27 — — — 25002.1 S-8 — 401 2 — A-7 L-58 1.13 100 0.3 S-1 2 402 4 — A-2 L-29 1.20 250.042 S-4 — 403 4 — A-2 L-48 1.20 25 0.042 S-3 — 404 1 C-43 — — — 10000.6 S-1 — 405 4 — A-2 L-12 1.20 25 0.042 S-1 — 406 1 C-25 — — — 100 0.3S-1 — 407 1 C-67 — — — 100 0.3 S-1 — 408 4 — A-4 L-32 1.20 25 0.042 S-1— 409 1 C-16 — — — 100 0.3 S-1 — 410 4 — A-2 L-48 1.20 25 0.042 S-4 —411 4 — A-5 L-36 1.20 25 0.042 S-7 — 412 6 — A-2 L-48 1.10 1500 6.53 S-10 413 1 C-66 — — — 100 0.3 S-1 — 414 4 — A-2 L-47 1.20 25 0.042 S-1 —415 6 — A-2 L-48 1.05 500 0.66 S-1 0 416 4 — A-4 L-31 1.20 25 0.042 S-1— 417 4 — A-5 L-15 1.20 25 0.042 S-1 — 418 1 C-27 — — — 2500 0.79 S-1 —419 4 — A-2 L-16 1.20 25 0.042 S-3 — 420 5 — A-2 L-48 1.05 2500 2.62 S-18 421 8 — A-2 L-48 1.05 2500 1.31 S-1 8 422 1 C-27 — — — 1000 0.6 S-1 —423 2 — A-7 L-57 1.13 100 0.3 S-1 2 424 5 — A-2 L-48 1.10 2500 21 S-1 60Diastereo-selectivity Solvent Solvent Concentration 1-a (R1 = Boc, 1-b(R1 = Boc, Volume Volume of 2-a (R1 = R2 = H, R2 = H, (Transition (Totalreaction Boc, R2 = H, Equivalents Tem- Reaction R3 = CO₂H or R3 = CO₂Hor Metal Catalyst) volume) R3 = CO₂H) Additive of perature Pressure TimeCO₂ ⁻) CO₂ ⁻) Method (ml) (ml) (mM) (D) Additive (° C.) (bar) (hours)(area % hplc) (area % hplc) 1 — 0.5 84.0 D-3 0.5 rt 7 16 88.8 11.2 2 —0.5 84.0 D-3 0.5 rt 7 16 93.9 6.1 3 — 3 100.0 — — 60 20 16 52.5 47.5 4 —0.5 84.0 — — rt 7 16 63.1 36.9 5 5 5 132.0 — — rt 7 16 49.2 50.8 6 — 0.584.0 — — rt 7 16 90.8 9.2 7 — 0.5 84.0 — — rt 20 16 60.7 39.3 8 — 3200.0 D-6 0.5 25 20 16 95.5 4.5 9 — 0.5 84.0 — — rt 20 16 48.2 51.8 10 —3 100.0 D-4 1 30 5 16 82.0 18.0 11 10 10 131.0 — — rt 7 16 92.1 7.9 12 —3 100.0 D-4 1 50 20 16 92.5 7.5 13 — 3 100.0 — — 50 20 16 46.5 53.5 14 420 131.0 — — rt 7 16 90.8 9.2 15 — 0.5 84.0 — — rt 7 16 34.6 65.4 16 —0.5 84.0 D-3 0.5 rt 7 16 91.5 8.5 17 — 3 200.0 D-7 1 25 20 16 93.0 7.018 — 3 200.0 D-6 0.5 25 20 16 95.5 4.5 19 — 0.5 84.0 — — rt 7 16 50.949.1 20 — 3 100.0 D-4 1 30 5 16 93.5 6.5 21 — 0.5 84.0 D-1 0.08 rt 20 1674.9 25.1 22 — 3 100.0 D-4 1 30 20 16 84.0 16.0 23 — 0.5 84.0 — — rt 2016 28.1 71.9 24 — 3 100.0 D-4 1 50 20 16 63.0 37.0 25 — 0.5 84.0 — — rt7 16 9.0 91.0 26 — 0.5 84.0 — — rt 20 16 61.8 38.2 27 — 3 100.0 — — 5020 16 52.5 47.5 28 — 0.5 84.0 — — rt 20 16 44.9 55.1 29 — 3 263.3 D-60.5 25 20 16 50.0 50.0 30 — 0.5 84.0 — — rt 20 16 92.9 7.1 31 — 3 100.0D-4 1 50 20 16 62.0 38.0 32 — 0.5 84.0 — — rt 20 16 78.9 21.1 33 — 0.584.0 — — rt 7 16 52.0 48.0 34 2 10 131.0 — — rt 15 16 92.2 7.8 35 — 3100.0 — — 50 20 16 62.5 37.5 36 — 0.5 84.0 — — rt 7 16 35.2 64.8 37 — 3100.0 — — 60 20 16 61.0 39.0 38 — 3 200.0 D-6 0.25 25 20 16 95.5 4.5 39— 3 100.0 D-4 1 60 20 16 73.5 26.5 40 — 0.5 84.0 — — rt 20 16 74.7 25.341 — 0.5 84.0 — — rt 7 16 9.8 90.2 42 1 3 100.0 — — 50 20 16 52.5 47.543 — 0.5 84.0 — — rt 7 16 75.1 24.9 44 — 0.5 84.0 — — rt 20 16 40.4 59.645 — 0.5 84.0 — — rt 20 16 77.7 22.3 46 — 3 100.0 D-4 1 50 20 16 41.558.5 47 — 3 263.3 D-6 0.9 25 20 16 95.5 4.5 48 5 5 132.0 — — rt 7 1681.9 18.1 49 — 3 263.3 D-6 0.5 25 20 16 96.0 4.0 50 — 0.5 84.0 — — rt 716 70.1 29.9 51 — 0.5 84.0 — — rt 7 16 79.5 20.5 52 — 0.5 84.0 — — rt 716 59.1 40.9 53 4 20 131.0 — — rt 7 16 95.2 4.8 54 2 10 131.0 — — 65 716 87.6 12.4 55 — 0.5 84.0 — — rt 20 16 61.6 38.4 56 15 15 33.3 — — rt15 16 74.0 26.0 57 — 0.5 84.0 — — rt 20 16 45.2 54.8 58 5 5 132.0 — — rt7 16 79.5 20.5 59 — 0.5 84.0 — — rt 20 16 10.5 89.5 60 — 0.5 84.0 — — rt20 16 80.7 19.3 61 — 0.5 84.0 — — rt 7 16 26.8 73.2 62 — 3 100.0 — — 6020 16 44.0 56.0 63 — 3 263.3 D-6 0.9 30 20 16 95.0 5.0 64 20 20 131.0 —— rt 7 16 94.0 6.0 65 4 20 131.0 — — rt 20 16 93.2 6.8 66 — 3 100.0 — —60 20 16 68.0 32.0 67 — 0.5 84.0 — — rt 20 16 31.9 68.1 68 4 20 131.0 —— rt 7 16 77.5 22.5 69 — 3 263.3 D-6 0.9 30 20 16 96.5 3.5 70 — 3 100.0D-4 1 50 20 16 78.5 21.5 71 — 0.5 84.0 — — rt 7 16 67.2 32.8 72 — 0.584.0 D-3 0.5 rt 7 16 88.1 11.9 73 — 3 100.0 — — 50 20 16 62.0 38.0 74 —3 100.0 D-4 1 60 20 16 70.0 30.0 75 10 85 262.5 — — rt 20 17 95.9 4.1 76— 3 200.0 D-4 0.5 25 20 16 93.5 6.5 77 5 5 132.0 D-3 0.1 rt 7 16 90.39.7 78 5 5 262.0 — — rt 7 16 85.3 14.7 79 4 20 131.0 — — rt 7 16 83.816.2 80 — 0.5 84.0 — — rt 20 16 57.2 42.8 81 — 0.5 84.0 — — rt 7 16 73.626.4 82 — 3 100.0 — — 60 20 16 73.5 26.5 83 — 0.5 84.0 — — rt 20 16 53.446.6 84 — 3 100.0 — — 50 20 16 41.0 59.0 85 — 0.5 84.0 — — rt 7 16 82.917.1 86 — 0.5 84.0 — — rt 7 16 26.0 74.0 87 — 3 100.0 D-4 1 50 20 1652.5 47.5 88 4 20 131.0 — — 65 7 16 92.7 7.3 89 20 20 131.0 — — rt 7 1693.9 6.1 90 — 8 262.5 D-8 0.9 25 20 18 94.0 6.0 91 — 3 100.0 D-4 1 60 2016 57.0 43.0 92 — 0.5 84.0 — — rt 7 16 76.4 23.6 93 — 3 100.0 — — 50 2016 56.5 43.5 94 — 0.5 84.0 D-1 0.08 rt 20 16 61.5 38.5 95 — 3 100.0 — —50 20 16 52.5 47.5 96 — 0.5 84.0 D-1 0.08 rt 20 16 56.3 43.7 97 — 3263.3 D-8 0.5 25 20 16 97.0 3.0 98 — 0.5 84.0 — — rt 7 16 84.1 15.9 99 —3 100.0 D-4 1 60 20 16 82.5 17.5 100 — 3 100.0 D-4 1 60 20 16 69.5 30.5101 — 0.5 84.0 — — rt 7 16 27.4 72.6 102 — 3 263.3 D-6 0.5 25 20 16 50.050.0 103 2 10 131.0 — — rt 7 16 94.6 5.4 104 — 0.5 84.0 — — rt 7 16 50.749.3 105 — 0.5 84.0 D-3 0.5 rt 7 16 90.4 9.6 106 — 0.5 84.0 — — rt 20 1671.3 28.7 107 — 3 100.0 D-4 1 30 5 16 84.0 16.0 108 — 0.5 84.0 — — rt 2016 43.5 56.5 109 — 0.5 84.0 D-1 0.08 rt 20 16 57.6 42.4 110 — 3 100.0 —— 60 20 16 34.0 66.0 111 — 0.5 84.0 — — rt 20 16 62.5 37.5 112 — 0.584.0 — — rt 7 16 82.8 17.2 113 60 160 131.3 — — rt 7 16 95.8 4.2 114 —0.5 84.0 — — rt 20 16 80.9 19.1 115 — 0.5 84.0 — — rt 7 16 65.9 34.1 116— 3 100.0 D-4 1 60 20 16 76.0 24.0 117 — 0.5 84.0 D-2 0.1 rt 7 16 12.887.2 118 — 0.5 84.0 — — rt 20 16 64.6 35.4 119 — 0.5 84.0 — — rt 7 1665.4 34.6 120 — 0.5 84.0 — — rt 20 16 41.4 58.6 121 — 3 100.0 — — 60 2016 39.0 61.0 122 — 0.5 84.0 — — rt 7 16 65.7 34.3 123 — 3 100.0 D-4 1 6020 16 61.0 39.0 124 — 3 100.0 D-4 1 50 20 16 83.0 17.0 125 — 0.5 84.0 —— rt 20 16 61.5 38.5 126 — 0.5 84.0 — — rt 20 16 55.7 44.3 127 — 0.584.0 — — rt 20 16 40.7 59.3 128 — 3 263.3 D-6 0.5 25 20 16 96.0 4.0 129— 0.5 84.0 — — rt 7 16 27.0 73.0 130 5 5 132.0 — — rt 7 16 96.4 3.6 131— 3 100.0 — — 50 20 16 26.0 74.0 132 — 0.5 84.0 — — rt 7 16 89.5 10.5133 — 3 100.0 — — 60 20 16 52.5 47.5 134 20 80 262.5 — — rt 7 16 93.16.9 135 — 0.5 84.0 D-1 0.08 rt 20 16 62.5 37.5 136 — 0.5 84.0 — — rt 716 84.2 15.8 137 — 0.5 84.0 — — rt 20 16 50.3 49.7 138 — 3 100.0 D-4 150 20 16 87.5 12.5 139 — 0.5 84.0 — — rt 7 16 42.7 57.3 140 — 0.5 84.0 —— rt 20 16 40.8 59.2 141 — 0.5 84.0 — — rt 7 16 60.7 39.3 142 — 0.5 84.0— — rt 7 16 34.6 65.4 143 — 8 262.5 D-6 0.9 35 20 18 96.0 4.0 144 — 3100.0 — — 60 20 16 52.5 47.5 145 — 3 263.3 D-6 0.5 25 20 16 50.0 50.0146 — 0.5 84.0 — — rt 20 16 63.0 37.0 147 — 0.5 84.0 — — rt 7 16 30.469.6 148 — 0.5 84.0 — — rt 20 16 67.7 32.3 149 — 3 100.0 — — 50 20 1634.0 66.0 150 — 3 100.0 D-4 1 60 20 16 52.5 47.5 151 — 0.5 84.0 D-2 0.1rt 7 16 34.4 65.6 152 — 3 100.0 — — 50 20 16 37.5 62.5 153 — 3 100.0 D-41 30 20 16 79.0 21.0 154 — 3 100.0 D-4 1 30 20 16 83.0 17.0 155 — 0.584.0 — — rt 7 16 93.1 6.9 156 — 0.5 84.0 — — rt 20 16 63.1 36.9 157 — 3100.0 — — 60 20 16 42.5 57.5 158 — 3 100.0 — — 60 20 16 75.0 25.0 159 —0.5 84.0 D-1 0.08 rt 20 16 71.6 28.4 160 — 3 100.0 — — 60 20 16 65.035.0 161 — 3 100.0 D-4 1 50 20 16 62.0 38.0 162 2 10 131.0 — — 65 7 1694.3 5.7 163 10 80 262.5 — — rt 20 16 92.1 7.9 164 30 90 131.1 — — rt 716 95.4 4.6 165 — 0.5 84.0 — — rt 20 16 48.2 51.8 166 — 3 263.3 D-6 0.525 20 16 96.0 4.0 167 — 0.5 84.0 — — rt 7 16 94.8 5.2 168 — 3 100.0 D-41 50 20 16 57.0 43.0 169 — 3 263.3 D-8 0.5 25 20 16 96.5 3.5 170 — 0.584.0 — — rt 20 16 39.9 60.1 171 — 3 100.0 D-4 1 50 20 16 85.0 15.0 172 —3 100.0 — — 60 20 16 81.0 19.0 173 — 0.5 84.0 — — rt 20 16 47.9 52.1 174— 0.5 84.0 — — rt 20 16 73.8 26.2 175 4 20 131.0 — — rt 14 16 81.5 18.5176 — 3 100.0 D-4 1 30 20 16 90.0 10.0 177 — 0.5 84.0 — — rt 7 16 79.120.9 178 — 0.5 84.0 — — rt 20 16 20.1 79.9 179 — 0.5 84.0 D-2 0.1 rt 716 36.4 63.6 180 — 3 100.0 D-4 1 50 20 16 91.5 8.5 181 2 10 131.0 — — 657 16 93.4 6.6 182 — 0.5 84.0 — — rt 7 16 37.8 62.2 183 — 3 100.0 — — 5020 16 83.0 17.0 184 — 3 263.3 D-6 0.5 25 20 16 96.0 4.0 185 — 3 200.0D-7 1 25 20 16 86.5 13.5 186 — 3 100.0 D-4 1 50 20 16 54.0 46.0 187 2 10131.0 — — rt 7 16 91.4 8.6 188 7 7 187.1 — — rt 7 16 87.9 12.1 189 — 3100.0 D-4 1 60 20 16 44.0 56.0 190 — 3 100.0 D-4 1 50 20 16 92.5 7.5 191— 3 100.0 D-4 1 50 20 16 57.0 43.0 192 2 10 131.0 — — 65 15 16 87.0 13.0193 — 3 100.0 D-4 1 30 20 16 84.5 15.5 194 2 10 131.0 — — rt 7 16 87.812.2 195 — 3 100.0 D-4 1 60 20 16 82.5 17.5 196 — 3 200.0 D-6 0.75 25 2016 95.5 4.5 197 — 3 263.3 D-6 0.9 25 20 16 97.0 3.0 198 — 0.5 84.0 — —rt 20 16 49.3 50.7 199 — 0.5 84.0 — — rt 20 16 71.1 28.9 200 — 0.5 84.0— — rt 20 16 28.2 71.8 201 2 10 131.0 — — rt 50 16 91.5 8.5 202 — 3200.0 D-7 0.5 25 20 16 92.5 7.5 203 2 10 262.0 — — rt 7 16 96.7 3.3 204— 3 100.0 — — 60 20 16 81.0 19.0 205 — 3 100.0 — — 60 20 16 47.0 53.0206 — 0.5 84.0 D-2 0.1 rt 7 16 28.4 71.6 207 — 0.5 84.0 — — rt 20 1663.9 36.1 208 — 3 100.0 — — 50 20 16 73.0 27.0 209 — 0.5 84.0 — — rt 2016 52.6 47.4 210 — 0.5 84.0 — — rt 20 16 43.5 56.5 211 — 0.5 84.0 D-10.08 rt 20 16 53.0 47.0 212 1 3 100.0 — — 50 20 16 52.5 47.5 213 4 20131.0 — — rt 7 16 89.6 10.4 214 1 3 100.0 — — 50 20 16 52.5 47.5 215 —0.5 84.0 — — rt 7 16 33.5 66.5 216 — 3 100.0 D-4 1 50 20 16 84.5 15.5217 — 0.5 84.0 — — rt 7 16 83.9 16.1 218 — 3 263.3 D-6 0.9 25 20 16 95.54.5 219 — 0.5 84.0 — — rt 7 16 9.9 90.1 220 — 3 100.0 D-4 1 60 20 1652.5 47.5 221 — 0.5 84.0 — — rt 7 16 33.2 66.8 222 — 0.5 84.0 — — rt 2016 78.5 21.5 223 — 3 100.0 D-4 1 50 20 16 94.0 6.0 224 — 0.5 84.0 — — rt7 16 89.9 10.1 225 — 0.5 84.0 — — rt 7 16 74.4 25.6 226 — 0.5 84.0 — —rt 20 16 94.1 5.9 227 — 3 100.0 D-4 1 60 20 16 60.5 39.5 228 — 3 200.0D-6 1 25 20 16 94.0 6.0 229 1 3 100.0 — — 50 20 16 44.5 55.5 230 — 3100.0 D-4 1 50 20 16 83.5 16.5 231 — 0.5 84.0 — — rt 7 16 86.1 13.9 2324 20 131.0 — — rt 1 16 94.9 5.1 233 — 0.5 84.0 — — rt 20 16 61.5 38.5234 — 0.5 84.0 — — rt 7 16 91.6 8.4 235 — 3 100.0 D-4 1 60 20 16 85.015.0 236 — 0.5 84.0 — — rt 7 16 80.3 19.7 237 — 0.5 84.0 — — rt 20 1651.6 48.4 238 — 3 100.0 — — 60 20 16 59.0 41.0 239 — 0.5 84.0 D-3 0.5 rt7 16 91.8 8.2 240 — 3 100.0 D-4 1 30 5 16 83.5 16.5 241 2 10 131.0 — —65 3 16 94.4 5.6 242 3 20 131.0 — — rt 7 16 95.5 4.5 243 — 0.5 84.0 D-30.5 rt 7 16 88.7 11.3 244 — 3 100.0 — — 50 20 16 50.0 50.0 245 — 0.584.0 — — rt 7 16 90.5 9.5 246 0.4 8.4 156.0 — — 65 15 16 87.0 13.0 247 —0.5 84.0 — — rt 20 16 70.3 29.7 248 — 0.5 84.0 — — rt 7 16 64.8 35.2 249— 0.5 84.0 D-1 0.08 rt 20 16 83.0 17.0 250 — 0.5 84.0 — — rt 20 16 65.934.1 251 — 0.5 84.0 — — rt 7 16 87.4 12.6 252 15 15 33.3 — — rt 15 1692.0 8.0 253 1 3 100.0 — — 50 20 16 62.0 38.0 254 — 3 100.0 D-4 1 50 2016 24.0 76.0 255 — 3 100.0 — — 60 20 16 58.5 41.5 256 — 3 100.0 D-4 1 6020 16 64.5 35.5 257 — 0.5 84.0 — — rt 7 16 24.2 75.8 258 4 20 131.0 — —rt 7 16 85.1 14.9 259 — 0.5 84.0 D-1 0.08 rt 20 16 63.9 36.1 260 — 0.584.0 — — rt 7 16 68.2 31.8 261 — 3 200.0 D-5 0.8 25 20 16 83.5 16.5 262— 3 263.3 D-6 0.9 25 20 16 96.5 3.5 263 — 0.5 84.0 — — rt 7 16 32.3 67.7264 — 0.5 84.0 — — rt 7 16 76.5 23.5 265 — 3 100.0 — — 60 20 16 52.547.5 266 8 8 163.8 — — rt 7 16 88.5 11.5 267 — 0.5 84.0 D-1 0.08 rt 2016 47.0 53.0 268 — 0.5 84.0 — — rt 7 16 44.6 55.4 269 — 3 100.0 — — 6020 16 56.0 44.0 270 — 0.5 84.0 — — rt 7 16 13.4 86.6 271 — 3 100.0 — —50 20 16 52.5 47.5 272 — 0.5 84.0 — — rt 20 16 68.8 31.2 273 — 3 100.0D-4 1 50 20 16 81.0 19.0 274 — 3 263.3 D-6 0.9 40 20 16 94.5 5.5 275 — 3200.0 D-5 0.8 25 20 16 84.0 16.0 276 — 3 100.0 D-4 1 60 20 16 61.5 38.5277 — 3 100.0 D-4 1 50 20 16 50.0 50.0 278 — 3 100.0 D-4 1 50 20 16 92.08.0 279 2 10 131.0 — — 65 20 16 93.3 6.7 280 8 8 163.8 — — rt 7 16 94.65.4 281 30 90 131.1 — — rt 7 16 95.3 4.7 282 — 0.5 84.0 — — rt 7 16 25.774.3 283 — 3 100.0 D-4 1 50 20 16 70.5 29.5 284 — 0.5 84.0 — — rt 20 1670.4 29.6 285 — 3 100.0 D-4 1 50 20 16 81.0 19.0 286 — 0.5 84.0 — — rt20 16 35.4 64.6 287 — 3 263.3 D-6 0.9 40 20 16 93.5 6.5 288 — 3 100.0D-4 1 50 20 16 87.0 13.0 289 — 3 263.3 D-6 0.5 25 20 16 97.0 3.0 290 —0.5 84.0 — — rt 7 16 64.4 35.6 291 — 0.5 84.0 — — rt 7 16 85.1 14.9 292— 3 200.0 D-6 1 25 20 16 95.0 5.0 293 — 3 200.0 D-6 0.1 25 20 16 95.54.5 294 — 3 100.0 — — 50 20 16 45.5 54.5 295 — 3 100.0 — — 60 20 16 30.070.0 296 — 3 200.0 D-6 0.5 25 20 16 93.5 6.5 297 — 3 100.0 — — 50 20 1647.5 52.5 298 — 3 200.0 D-7 0.5 25 20 16 95.0 5.0 299 — 0.5 84.0 — — rt7 16 89.7 10.3 300 — 3 100.0 D-4 1 30 20 16 78.0 22.0 301 — 3 263.3 D-80.5 25 20 16 96.5 3.5 302 — 0.5 84.0 — — rt 20 16 11.8 88.2 303 — 0.584.0 — — rt 20 16 56.6 43.4 304 — 3 100.0 D-4 1 50 20 16 85.5 14.5 305 —3 100.0 — — 60 20 16 59.0 41.0 306 — 3 100.0 D-4 1 60 20 16 66.5 33.5307 — 3 200.0 D-4 1 50 20 16 91.5 8.5 308 — 0.5 84.0 — — rt 7 16 89.610.4 309 — 3 100.0 D-4 1 50 20 16 89.0 11.0 310 1 3 100.0 — — 50 20 1652.5 47.5 311 — 3 100.0 D-4 1 30 5 16 91.0 9.0 312 — 3 100.0 D-4 1 60 2016 52.5 47.5 313 — 0.5 84.0 D-3 0.5 rt 7 16 88.3 11.7 314 — 3 100.0 D-41 60 20 16 46.0 54.0 315 — 0.5 84.0 — — rt 7 16 50.8 49.2 316 60 20013.1 — — rt 7 16 95.1 4.9 317 — 3 100.0 — — 60 20 16 52.5 47.5 318 — 0.584.0 — — rt 20 16 38.7 61.3 319 — 3 100.0 D-4 1 50 20 16 37.5 62.5 320 —3 100.0 — — 50 20 16 29.0 71.0 321 — 0.5 84.0 — — rt 7 16 28.8 71.2 322— 3 100.0 D-4 1 60 20 16 68.5 31.5 323 10 10 131.0 — — rt 7 16 93.9 6.1324 — 0.5 84.0 — — rt 7 16 54.4 45.6 325 — 0.5 84.0 — — rt 20 16 62.038.0 326 — 3 100.0 — — 60 20 16 69.5 30.5 327 — 3 100.0 — — 50 20 1652.5 47.5 328 — 0.5 84.0 — — rt 7 16 11.9 88.1 329 2 10 131.0 — — 65 116 94.7 5.3 330 — 3 100.0 — — 50 20 16 60.0 40.0 331 — 3 263.3 D-8 0.925 20 16 96.5 3.5 332 — 3 100.0 D-4 1 60 20 16 63.5 36.5 333 — 3 100.0 —— 50 20 16 42.5 57.5 334 — 3 100.0 — — 50 20 16 63.0 37.0 335 2 10 131.0— — rt 20 16 87.3 12.7 336 — 3 200.0 D-4 1 25 20 16 94.0 6.0 337 — 3263.3 D-8 0.5 25 20 16 96.0 4.0 338 — 3 100.0 — — 50 20 16 51.5 48.5 339— 3 100.0 — — 50 20 16 40.5 59.5 340 — 3 100.0 D-4 1 50 20 16 75.0 25.0341 — 3 200.0 D-4 0.5 25 20 16 95.0 5.0 342 — 0.5 84.0 D-1 0.08 rt 20 1667.8 32.2 343 — 0.5 84.0 — — rt 20 16 73.2 26.8 344 2 10 131.0 — — rt 116 94.7 5.3 345 — 3 100.0 D-4 1 30 20 16 94.0 6.0 346 — 0.5 84.0 — — rt7 16 72.0 28.0 347 — 3 100.0 — — 50 20 16 62.0 38.0 348 4 20 131.0 — —rt 14 16 81.5 18.5 349 — 0.5 84.0 D-1 0.08 rt 20 16 54.0 46.0 350 — 3100.0 D-4 1 60 20 16 73.5 26.5 351 — 8 262.5 D-6 0.9 25 20 18 97.0 3.0352 — 3 100.0 D-4 1 50 20 16 58.0 42.0 353 — 0.5 84.0 — — rt 20 16 46.353.7 354 — 0.5 84.0 — — rt 20 16 77.5 22.5 355 — 0.5 84.0 — — rt 20 1682.6 17.4 356 — 0.5 84.0 — — rt 20 16 75.2 24.8 357 — 0.5 84.0 — — rt 2016 31.3 68.7 358 — 3 100.0 — — 50 20 16 86.5 13.5 359 60 160 131.3 — —rt 7 16 93.9 6.1 360 — 0.5 84.0 — — rt 7 16 77.5 22.5 361 — 0.5 84.0 — —rt 20 16 54.6 45.4 362 — 0.5 84.0 D-3 0.5 rt 7 16 76.2 23.8 363 — 0.584.0 — — rt 20 16 69.3 30.7 364 — 0.5 84.0 — — rt 20 16 93.3 6.7 365 — 3100.0 — — 50 20 16 39.5 60.5 366 60 160 8.2 — — rt 7 16 95.2 4.8 367 210 131.0 — — 65 7 16 93.2 6.8 368 — 3 100.0 D-4 1 50 20 16 89.0 11.0 369— 3 100.0 D-4 1 50 20 16 86.5 13.5 370 — 3 100.0 — — 60 20 16 40.0 60.0371 — 0.5 84.0 — — rt 20 16 76.6 23.4 372 — 3 100.0 D-4 1 50 20 16 82.517.5 373 10 10 131.0 — — rt 7 16 87.9 12.1 374 — 0.5 84.0 — — rt 20 1690.9 9.1 375 — 0.5 84.0 — — rt 20 16 70.6 29.4 376 — 3 200.0 D-4 1 25 2016 94.5 5.5 377 — 0.5 84.0 — — rt 20 16 92.0 8.0 378 — 0.5 84.0 — — rt 716 75.0 25.0 379 — 3 100.0 D-4 1 60 20 16 66.5 33.5 380 — 0.5 84.0 — —rt 20 16 92.2 7.8 381 4 20 131.0 — — 45 7 16 83.1 16.9 382 — 0.5 84.0 —— rt 7 16 32.3 67.7 383 — 3 100.0 — — 60 20 16 67.5 32.5 384 — 0.5 84.0— — rt 20 16 53.2 46.8 385 — 0.5 84.0 — — rt 20 16 74.5 25.5 386 — 0.584.0 D-3 0.5 rt 7 16 40.7 59.3 387 — 0.5 84.0 — — rt 20 16 41.2 58.8 388— 3 100.0 — — 60 20 16 68.0 32.0 389 — 0.5 84.0 D-1 0.08 rt 20 16 54.345.7 390 3 15 87.3 — — rt 1 16 94.5 5.5 391 — 0.5 84.0 D-1 0.08 rt 20 1650.6 49.4 392 — 0.5 84.0 — — rt 20 16 62.6 37.4 393 — 0.5 84.0 — — rt 2016 52.7 47.3 394 — 0.5 84.0 — — rt 20 16 60.3 39.7 395 5 5 132.0 D-3 0.5rt 7 16 84.9 15.1 396 — 0.5 84.0 — — rt 20 16 93.7 6.3 397 — 0.5 84.0 —— rt 20 16 66.4 33.6 398 — 0.5 84.0 — — rt 7 16 89.2 10.8 399 — 3 100.0— — 50 20 16 70.5 29.5 400 — 8 262.5 D-6 0.9 40 20 18 94.5 5.5 401 1 3100.0 — — 50 20 16 52.5 47.5 402 — 0.5 84.0 D-2 0.1 rt 7 16 73.2 26.8403 — 0.5 84.0 — — rt 7 16 94.8 5.2 404 — 3 200.0 D-4 1 50 20 16 78.022.0 405 — 0.5 84.0 — — rt 7 16 79.7 20.3 406 — 3 100.0 D-4 1 50 20 1687.5 12.5 407 — 3 100.0 — — 50 20 16 46.0 54.0 408 — 0.5 84.0 — — rt 2016 28.6 71.4 409 — 3 100.0 D-4 1 50 20 16 47.5 52.5 410 — 0.5 84.0 D-20.1 rt 7 16 62.1 37.9 411 — 0.5 84.0 D-2 0.1 rt 7 16 72.3 27.7 412 25 25261.2 — — rt 7 16 94.7 5.3 413 — 3 100.0 — — 50 20 16 67.0 33.0 414 —0.5 84.0 — — rt 20 16 88.8 11.2 415 5 5 132.0 D-2 0.5 rt 7 16 39.2 60.8416 — 0.5 84.0 — — rt 20 16 55.7 44.3 417 — 0.5 84.0 — — rt 20 16 71.328.7 418 — 3 263.3 D-8 0.9 25 20 16 96.5 3.5 419 — 0.5 84.0 D-3 0.5 rt 716 26.0 74.0 420 2 10 262.0 — — rt 7 16 94.6 5.4 421 2 10 131.0 — — rt 716 91.5 8.5 422 — 3 200.0 D-5 0.8 25 20 16 91.5 8.5 423 1 3 100.0 — — 5020 16 56.5 43.5 424 20 80 262.5 — — rt 20 16 95.5 4.5

For the purpose of Example 43, the following abbreviations apply:

Organometallic Catalyst (C)C-1=[Rh(COD)(SL-P005-1)]BF₄=[Rh(COD)(L-38)]BF₄C-2=[Rh(COD)(SL-P102-1)]O₃SCF₃=[Rh(COD)(L-40)]O₃SCF₃C-3=[Rh(COD)(SL-P102-1)]BF₄=[Rh(COD)(L-40)]BF₄C-4=[Rh(COD)(SL-P104-2)]O₃SCF₃=[Rh(COD)(L-41)]O₃SCF₃ C-5=[(S)MeBoPhozRh(COD)]BF₄=[(L-55)Rh(COD)]BF₄ C-6=[(R)4—F—C6H4-MeBoPhozRu(benzene)Cl]Cl=[(L-60)Ru(benzene)Cl]Cl

C-7=[(R)Phenethyl-(R)-MeBoPhoz Ru(benz ene)Cl]Cl=[(L-61)Ru(benzene)Cl]Cl

C-8=(R)BINOL-(R)-MeBoPhoz Ru(benzene)Cl]Cl=[(L-62)Ru(benzene)Cl]ClC-9=[(S)BINOL-(R)-MeBoPhoz Ru(benzene)Cl]Cl=[(L-63)Ru(benzene)Cl]ClC-10=[(R)MeBoPhoz RuCl(Benzene)]Cl=[(L-54)RuCl(Benzene)]ClC-11=[(R)_(p)—F-MeBoPhoz RuCl(Benzene)]Cl=[(L-64)RuCl(Benzene)]ClC-12=[(S)MeBoPhoz Ir(COD)]Cl=[(L-55)Ir(COD)]Cl C-13=[(R)MeBoPhozIr(COD)]Cl=[(L-54)Ir(COD)]Cl C-14=[(R,R)BDPPRh(COD)]BF₄=[(L-65)Rh(COD)]BF₄ C-15=[(S,S)BDPPRh(COD)]BF₄=[(L-66)Rh(COD)]BF₄ C-16=[(R)Binam-PRh(COD)]BF₄=[(L-67)Rh(COD)]BF₄ C-17=[(S)Binam-PRh(COD)]BF₄=[(L-68)Rh(COD)]BF₄ C-18=[(R)Tol-BINAPRuCl(benzene)]Cl=[(L-69)RuCl(benzene)]Cl C-19=[(S)Tol-BinapRh(COD)]BF₄=[(L-70)Rh(COD)]BF₄

C-20=[(R)Binap RuCl(benzene)]Cl=[(L-71)(benzene)]ClC-21=[(S)Binap RuCl(benzene)]Cl=[(L-72)(benzene)]Cl

C-22=[(S)BINAP Rh(COD)]BF₄=[(L-72)Rh(COD)]BF₄ C-23=[(R)BinaphaneRh(COD)]BF₄=[(L-73)Rh(COD)]BF₄ C-24=[(S,S)Me-BPERh(COD)]BF₄=[(L-74)Rh(COD)]BF₄ C-25=[(S,S)Ph-BPERh(COD)]BF₄=[(L-75)Rh(COD)]BF₄ C-26=[(R)CatASium DRh(COD)]BF₄=[(L-76)Rh(COD)]BF₄ C-27=[(R)CatASium MRh(COD)]BF₄=[(L-77)Rh(COD)]BF₄ C-28=[(R)CatASium MNRh(COD)]BF₄=[(L-78)MN Rh(COD)]BF₄ C-29=[(R)CatASium MNNRh(COD)]BF₄=[(L-79)MNN Rh(COD)]BF₄ C-30=[(S)CatASium MRh(COD)]BF₄=[(L-80)M Rh(COD)]BF₄ C-31=[(S)CatASium MNRh(COD)]BF₄=[(L-81)Rh(COD)]BF₄ C-32=[(S,S)ChiraPhosRh(COD)]BF₄=[(L-82)Rh(COD)]BF₄ C-33=[(R,R)DIOPRh(COD)]BF₄=[(L-83)Rh(COD)]BF₄ C-34=[(S,S)DIOPRh(COD)]BF₄=[(L-84)Rh(COD)]BF₄ C-35=[(R,R)DIPAMPRh(COD)]BF₄=[(L-85)Rh(COD)]BF₄ C-36=[(R,R)DuanPhosRh(COD)]BF₄=[(L-86)Rh(COD)]BF₄ C-37=[(R)MeDuPhosRh(COD)]BF₄=[(L-87)Rh(COD)]BF₄ C-38=[(S,S)Et-FerrotaneRh(COD)]BF₄=[(L-88)Rh(COD)]BF₄ C-39=[(R,R)NorPhosRh(COD)]BF₄=[(L-89)Rh(COD)]BF₄ C-40=[(S,S)NorPhosRh(COD)]BF₄=[(L-90)Rh(COD)]BF₄ C-41=[(R)PhanePhosRh(COD)]BF₄=[(L-91)Rh(COD)]BF₄ C-42=[(S)PhanePhosRh(COD)]BF₄=[(L-92)Rh(COD)]BF₄ C-43=[(R)Xyl-PhanePhosRh(COD)]BF₄=[(L-92)Rh(COD)]BF₄

C-44=[(R)Xyl-PhanePhos RuCl₂(dmf)₂]=[(L-93)RuCl₂(dmf)₂]C-45=[(S)Xyl-PhanePhos RuCl₂(dmf)₂]=[(L-94)RuCl₂(dmf)₂]C-46=[(R)PhanePhos RuCl₂(dmf)₂]=[(L-91)RuCl₂(dmf)₂]

C-47=[(R)An-PhanePhos Rh(COD)]BF₄=[(L-96)Rh(COD)]BF₄C-48=[(R)MeO-Xyl-PhanePhos Rh(COD)]BF₄=[(L-97)Rh(COD)]BF₄C-49=[(R)Tol-PhanePhos Rh(COD)]BF₄=[(L-95)Rh(COD)]BF₄ C-50=[(S)iPr-PHOXIr(COD)]BArF=[(L-98)Ir(COD)]BArF C-51=[(S)Cy-tBu-SIMPLEPHOXIr(COD)]BArF=[(L-99)Ir(COD)]BArF C-52=[(R)P-PhosRh(COD)]BF₄=[(L-100)Rh(COD)]BF₄ C-53=[(S)P-PhosRh(COD)]BF₄=[(L-101)Rh(COD)]BF₄

C-54=[(R)Xyl-P-Phos RuCl₂(dmf)₂]=[(L-102)RuCl₂(dmf)₂]C-55=[(S)Xyl-P-Phos RuCl₂(dmf)₂]=[(L-103)RuCl₂(dmf)₂]

C-56=[(S)P-Phos RuCl(benzene)]Cl=[(L-101)RuCl(benzene)]ClC-57=[(R)P-Phos RuCl(benzene)]Cl=[(L-100)RuCl(benzene)]ClC-58=[(R)P-Phos Ru(acac)₂]=[(L-100)Ru(acac)₂] C-59=[(R)Xyl-P-PhosRu(acac)₂]=[(L-102)Ru(acac)₂] C-60=[(R)Xyl-P-PhosRuCl(benzene)]Cl=[(L-102)RuCl(benzene)]Cl C-61=[(S)P-PhosIr(COD)]Cl=[(L-101)Ir(COD)]Cl C-62=[(S)Xyl-P-PhosIr(COD)Cl=[(L-103)Ir(COD)]Cl C-63=[(R)ProPhosRh(COD)]BF₄=[(L-104)Rh(COD)]BF₄

C-64=[(R_(a),S_(c))1Np-QUINAPHOS RuCl₂(dmf)₂]=[(L-105)RuCl₂(dmf)₂]C-65=[(S_(a),R_(c))1Np-QUINAPHOS RuCl₂(dmf)₂]=[(L-106)RuCl₂(dmf)₂]

C-66=[(S,S,R,R)TangPhos Rh(COD)]BF₄=[(L-107)Rh(COD)]BF₄C-67=[(R)-JafaPhos Rh(COD)]BF₄=[(L-108)Rh(COD)]BF₄ OrganometallicComplex (A) A-1=[Ir(COD)Cl]₂ A-2=[Rh(NBD)₂]BF₄

A-3=[Ru(COD)(2-metallyl)₂]

A-4=[Ru(COD)(OOCCF₃)₂]

A-5=[RuI₂(p-cymene)]₂

A-6=[(Cy₃P)Ir(pyr)]Cl A-7=[Rh(COD)₂]BF₄ Chiral Ligand (L)L-1=Atropisomer SL-A101-1 L-2=Atropisomer SL-A109-2 L-3=AtropisomerSL-A116-2 L-4=Atropisomer SL-A118-1 L-5=Atropisomer SL-A132-2L-6=Fenphos SL-F131-1 L-7=Fenphos SL-F132-1 L-8=Fenphos SL-F133-1L-9=Fenphos SL-F134-1 L-10=Fenphos SL-F135-1 L-11=Fenphos SL-F355-1L-12=Fenphos SL-F356-1 L-13=Fenphos SL-F365-1 L-14=Josiphos SL-J005-2L-15=Josiphos SL-J008-1 L-16=Josiphos SL-J009-1 L-17=Josiphos SL-J013-1L-18=Josiphos SL-J211-1 L-19=Josiphos SL-J301-1 L-20=Josiphos SL-J403-1L-21=Josiphos SL-J408-1 L-22=Josiphos SL-J412-1 L-23=Josiphos SL-J430-1L-24=Josiphos SL-J431-1 L-25=Josiphos SL-J501-1 L-26=Josiphos SL-J503-1L-27=Josiphos SL-J504-1 L-28=Josiphos SL-J504-2 L-29=Josiphos SL-J505-2L-30=Josiphos SL-J506-1 L-31=Mandyphos SL-M002-1 L-32=MandyphosSL-M003-1 L-33=Mandyphos SL-M004-1 L-34=Mandyphos SL-M004-2L-35=Mandyphos SL-M009-1 L-36=Mandyphos SL-M010-1 L-37=MandyphosSL-M012-1 L-38=Phospholane SL-P005-1 L-39=Phospholane SL-P051-1L-40=Phospholane SL-P102-1 L-41=Phospholane SL-P104-2 L-42=TaniaphosSL-T001-1 L-43=Taniaphos SL-T001-2

L-44=Taniaphos. SL-T003-1

L-45=Taniaphos SL-T021-2 L-46=Walphos SL-WO01-1 L-47=Walphos SL-WO05-1L-48=Walphos SL-WO08-1 L-49=Walphos SL-WO08-2 L-50=Walphos SL-WO09-1L-51=Walphos SL-WO12-1 L-52=Walphos SL-WO21-1 L-53=Walphos SL-WO24-1L-54=(R)-MeBophoz L-55=(S)-MeBoPhoz L-56=(R)-3,5-F2C6H3-BnBoPhozL-57=(R)-Cy-MeBoPhoz L-58=(R)-Phenethyl-(R)-BoPhozL-59=(R)-Phenethyl-(S)-BoPhoz L-60=(R)-4-F—C6H4-MeBoPhozL-61=(R)-Phenethyl-(R)-MeBoPhoz L-62=(R)-BINOL-(R)-MeBoPhozL-63=(S)-BINOL-(R)-MeBoPhoz L-64=(R)-p-F-MeBoPhoz L-65=(R,R)-BDPPL-66=(S,S)-BDPP L-67=(R)BINAM-P L-68=(S)-BINAM-P L-69=(R)-Tol-BINAPL-70=(S)-Tol-BINAP L-71=(R)-BINAP L-72=(S)-BINAP L-73=(R)-BinaphaneL-74=(S,S)-Me-BPE L-75=(S,S)-Ph-BPE L-76=(R)-CatASium DL-77=(R)-CatASium M L-78=(R)-CatASium MN L-79=(R)-CatASium MNNL-80=(S)-CatASium M L-81=(S)-CatASium MN L-82=(S,S)-ChiraPhosL-83=(R,R)-DIOP L-84=(S,S)-DIOP L-85=(R,R)-DIPAMP L-86=(R,R)-DuanPhosL-87=(R)-MeDuPhos L-88=(S,S)-Et-Ferrotane L-89=(R,R)-NorPhosL-90=(S,S)-NorPhos L-91=(R)-PhanePhos L-92=(S)-PhanePhosL-93=(R)-Xyl-PhanePhos L-94=(S)-Xyl-PhanePhos L-95=(R)-Tol-PhanePhosL-96=(R)-An-PhanePhos L-97=(R)-MeO-Xyl-PhanePhos L-98=(S)-iPr-PHOXL-99=(S)-Cy-tBu-SIMPLEPHOX L-100=(R)—P-Phos L-101=(S)—P-PhosL-102=(R)-Xyl-P-Phos L-103=(S)-Xyl-P-Phos L-104=(R)-ProPhosL-105=(R_(a),S_(c))-1Np-QUINAPHOS L-106=(S_(a),R_(c))-1Np-QUINAPHOSL-107=(S,S,R,R)TangPhos

L-108=(R)-JafaPhos(=(R)-(+)-1,1′-Bis(diphenylphosphino)-2,2′-bis(N,N-diisopropylamido)ferrocene)

Solvent (S) S-1: Ethanol S-2: Methanol S-3: Ethanol/Isopropanol (1:1)S-4: Ethanol/Trifluoroethanol/2-Methyltetrahydrofuran (48:47:5) S-5:Ethanol/Isopropanol (18:1) S-6: Trifluoroethanol/Ethanol (1:1) S-7:2-Methyltetrahydrofuran/Ethanol (5:95) S-8: Isopropanol S-9:Dichloroethane

S-10: Ethyl acetate

S-11: Tetrahydrofuran S-12: 2-Methyltetrahydrofuran S-13: Ethanol/Water(7:3) Additive (D)

D-1: Tetrafluoroboric acid etherateD-2: Methanesulphonic acidD-3: 1,4-Diazobicyclo[2.2.2]octane

D-4: Triethylamine

D-5: Potassium ethoxide

D-6: Diisopropylethylamine D-7: 1,1,3,3-Tetramethylguanidine

D-8: Sodium methoxide

Example 44(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H)

For a given reaction, after the reaction time indicated in the tableshown in Example 43, the solvent may be optionally removed, for example,under reduced pressure. The residue may then be used in subsequenttransformations.

Method 1

Ethanol (1.2 ml) is added to the reaction concentrate obtained fromExample 43, Method 351 (240 mg). The mixture is heated to reflux. Water(0.6 ml) and acetic acid (43 μl) are added. The mixture is cooled to 0°C. and stirred at this temperature for 1 h. The solid is collected byfiltration and washed with an ethanol-water mixture (2 ml, 2:1). Thesolid is then dried under vacuum to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H). Ratio of diastereomers 99.8:0.2 (1-a,R1=Boc, R2=H, R3=CO₂H:1-a, R1=Boc, R2=H, R3=CO₂H) from hplc.

Method 2

Isopropyl acetate (1.5 ml) is added to the reaction concentrate obtainedfrom Example 43, Method 351 (240 mg). Citric acid (145 mg) dissolved inwater (1.3 ml) is added. The phases are separated. The organic phase iswashed with water (1.5 ml). The phases are then separated. The organicphase is then concentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-b, R1=Boc, R2=H, R3=CO₂H). Ratio of diastereomers 97.7:2.3 (1-a,R1=Boc, R2=H, R3=CO₂H:1-a, R1=Boc, R2=H, R3=CO₂H) from hplc.

Optionally, the material obtained from General Procedures 1 and 2 can besubsequently and repeatedly recrystallised, for example, by followingGeneral Procedure 3.

Method 3

A mixture of 174 mg(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) obtained from Example 44, Method 2 inisopropyl acetate (350 μl) is heated to give a solution. Heptane (700μl) is added. The mixture is cooled to 0° C. and stirred at thistemperature for 1 h. The solid is collected by filtration and washedwith an isopropyl acetate: heptane mixture (1 ml, 1:2). The solid isthen dried under vacuum to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2H, R3=CO₂H). Ratio of diastereomers 99.9:0.1 (1-a,R1=Boc, R2=H, R3=CO₂H: 1-a, R1=Boc, R2=H, R3=CO₂H) from hplc.

Performing of reactions in accordance with Methods 1, 2 or 3 isindependent of whether an additive, for example, a base, is used duringthe reaction given in Example 41. Reactions performed in the absence ofa base may also be subsequently processed according to methods given inMethods 1, 2 or 3. Alternatively, they may be processed according tomethods described in WO2008/031567, for example, Examples 2 or 3

HPLC Method (reactions performed according to Example 44, Methods 1, 2or 3)

Column: Daicel QN-AX; 150×4.6 mm; 5 μm. Mobile Phase A: Methanol-Ethanol(1:1), 0.1% AcOH (v/v), 0.1% NH₄OAc (m/v). Isocratic: 0 min (100% A); 20min (100% A). Flow rate: 0.5 ml min⁻¹. Wavelength: 254 nm. Columntemperature: 10° C.

Retention times:

(1-a, R1=Boc, R2=H, R3=CO₂H):7.8 min (1-b, R1=Boc, R2=H, R3=CO₂H):10.3min (2-a, R1=Boc, R2=H, R3=CO₂H):14.3 min Example 45 (3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (3-b, R1=Boc)

Method 1

Ethanol (1 ml) is added to a mixture of 100 mg(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) and 10% palladium on carbon (10 mg,50% water wet, Degussa type E101 NE/W). Hydrogen gas is applied to themixture. The mixture is stirred at ambient temperature and pressure for24 h. The mixture is then filtered over Celites and washed with ethanol(2×0.5 ml). The mixture is then concentrated in vacuo to give(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 20:80 (3-a,R1=Boc: 3-b, R1=Boc) as determined by hplc. Spectroscopic data indescribed in WO/2008/083967, for example, Examples 14 and 18.

Method 2

Isopropyl acetate (1 ml) is added to a mixture of 100 mg(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) and 10% palladium on carbon (10 mg,50% water wet, Degussa type E101 NE/W). Hydrogen gas is applied to themixture. The mixture is stirred at ambient temperature and pressure for24 h. The mixture is then filtered over Celite and washed with isopropylacetate (2×0.5 ml). The mixture is then concentrated in vacuo to give(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 15:85 (3-a,R1=Boc): 3-b, R1=Boc) as determined by hplc. Spectroscopic data indescribed in WO/2008/083967, for example, Examples 14 and 18.

Method 3

Isopropyl acetate (1 ml) is added to a mixture of 100 mg(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) and 10% platinium on carbon (10 mg).Hydrogen gas (ambient pressure) is applied to the mixture. The mixtureis stirred at ambient temperature and pressure for 4 h. The mixture isthen filtered over Celites and washed with isopropyl acetate (2×0.5 ml).The mixture is then concentrated in vacuo to give(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 33:67 (3-a,R1=Boc: 3-b, R1=Boc) as determined by hplc. Spectroscopic data indescribed in WO/2008/083967, for example, Examples 14 and 18.

Method 4

Isopropyl acetate (1 ml) is added to a mixture of 100 mg(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) and 10% rhodium on carbon (10 mg).Hydrogen gas (ambient pressure) is applied to the mixture. The mixtureis stirred at ambient temperature and pressure for 50 h. The mixture isthen filtered over Celites and washed with isopropyl acetate (2×0.5 ml).The mixture is then concentrated in vacuo to give(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 21:79 (3-a,R1=Boc: 3-b, R1=Boc) as determined by hplc. Spectroscopic data indescribed in WO/2008/083967, for example, Examples 14 and 18.

HPLC Method 1 (Methods 1-4)

Column: AD-RH Chiralpak; 150×4.6 mm. Mobile Phase A (water); MobilePhase B (Acetonitrile). Isocratic: 0 min (20% B); 15 min (20% B). Flowrate: 0.5 ml min⁻¹. Wavelength 210 nm. Column temperature: 40° C.

Retention times:

(3-a, R1=Boc): 6.2 min (3-b, R1=Boc): 6.8 min HPLC Method 2 (Methods1-4)

Column: Zorbax SB-C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.01 M KH₂PO₄in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (30% B); 10min (80% B); 15 min (80% B); 15.1 min (30% B); 18 min (30% B). Flowrate: 1.0 ml min⁻¹. Wavelength: 210 nm. Temperature 50° C.

Retention times:

(4-a, R1=Boc): 9.8 min (3-a, R1=Boc; 3-b, R1=Boc): 10.1 min Example 46(3R, 5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (3-b, R1=Boc)

General Procedure for Methods 1-7

To a mixture of 0.5 mmol(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) in methanol or ethanol (5 ml) atambient temperature, a solution of Organometallic Complex (S/C ratio of50 or 100) and Chiral Ligand (1.1 eq per metal atom within theorganometallic complex) is added in methanol or ethanol (5 ml). Ahydrogen pressure of 20 bar is applied for 20 h at ambient temperature.The solvent is then removed in vacuo to provide the correspondingproduct. The samples are analysed by hplc to determine the ratio of(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc) to(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc). Spectroscopic data in described inWO/2008/083967, for example, Examples 14 and 18.

Method 1

Chiral Ligand{(S)-(−)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)-bis(diphenylphosphine)=(S)-Ph-MeOBIPHEP=SL-A101-2};Organometallic Complex {dichloro(p-cymene)ruthenium(II) dimer}; Ethanol.Diastereomer ratio 82:18 (3-a, R1=Boc: 3-b, R1=Boc) as determined byhplc.

Method 2

Chiral Ligand {(αS,αS)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene=(S)—(R)—NMe₂-P(3,5-Me-4-MeOPh)-2-Mandyphos=SL-M004-2};Organometallic Complex {dichloro(p-cymene)ruthenium(II) dimer}; Ethanol.Diastereomer ratio 82:18 (3-a, R1=Boc: 3-b, R1=Boc) as determined byhplc.

Method 3

Chiral Ligand{(R)-1-[(S)-2-Di-cyclohexylphosphino)ferrocenyl]ethyldi-(2-methylphenyl)phosphine=(R)—(S)-Cy₂PF—P°Tol₂=SL-J504-1}; Organometallic Complex{dichloro(p-cymene)ruthenium(II) dimer}; Methanol. Diastereomer ratio53:47 (3-a, R1=Boc: 3-b, R1=Boc) as determined by hplc.

Method 4

Chiral Ligand{(R,R)-2,2″-Bis[(S)-1-(diarylphosphino)ethyl]-1,1″-biferrocene=SL-F115-1};Organometallic Complex {bis(norbornadiene)rhodium(I) tetrafluoroborate};Methanol. Diastereomer ratio 71:29 (3-a, R1=Boc: 3-b, R1=Boc) asdetermined by hplc.

Method 5

Chiral Ligand{(S-1-[(R)-2-Diphenylphosphinoferrocenyl]ethyldi-tert.-butylphosphine=(S)—(R)—PPF—PtBu₂=SL-J002-2};Organometallic Complex{bis(trifluoroacetoxy)(1,5-cyclooctadiene)ruthenium(II)}; Methanol.Diastereomer ratio 56:44 (3-a, R1=Boc: 3-b, R1=Boc) as determined byhplc.

Method 6

Chiral Ligand{(R)-1-[(R)-2-(2′-Dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-(3,5-trifluoromethyl)phenyl)phosphine=(R)—(R)-cy₂PPhFCHCH₃P(3,5-CF₃Ph)₂=SL-WO08-1-1};Organometallic Complex {bis(norbornadiene)rhodium(1) tetrafluoroborate};Methanol. Diastereomer ratio 27:73 (3-a, R1=Boc: 3-b, R1=Boc) asdetermined by hplc.

Method 7

Chiral Ligand{(S-1-[(R)-2-Diphenylphosphinoferrocenyl]ethyldi-tert.-butylphosphine=(S)—(R)—PPF—PtBu₂=SL-J002-2};Organometallic Complex {dichloro(p-cymene)ruthenium(II) dimer};Methanol. Diastereomer ratio 61:39 (3-a, R1=Boc: 3-b, R1=Boc) asdetermined by hplc.

HPLC Method (Methods 1-7)

Column: Gemini C6 Phenyl; 150×3.0 mm; 3.0 μm. Mobile Phase A (0.01 MKH₂PO₄ in water); Mobile Phase B (Methanol). Gradient: 0 min (40% B); 5min (70% B); 12 min (70% B); 13 min (80% B); 21 min (80% B); 21.1 min(40% B); 25 min (40% B). Flow rate: 0.7 ml Wavelength: 210 nm.Temperature 50° C.

Retention times:

(4-a, R1=Boc): 12.3 min (3-a, R1=Boc): 12.9 min (3-b, R1=Boc): 13.2 minExample 47(3R/S,5S)-biphenyl-4-ylmethyl-3-dimethylaminomethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (9-a, R1=Boc, R6=Me, R7=Me)

General Procedure for Methods 1-178

Solvent is added to a vessel containing(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) to achieve a finalconcentration as indicated in the Table of Example 47 (Methods 1-178).

Optionally and according to the table, an additive may be added at thisstage. The identity and amount of the additive is given in the Table ofExample 47 (Methods 1-178). The amount of additive to be used isrelative to the moles of(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) used.

The catalyst is then added. The type and amount of catalyst used isgiven in the Table of Example 47 (Methods 1-178).

Hydrogen gas is applied to the vessel containing the mixture at thepressure given in the Table of Example 47 (Methods 1-178). The mixtureis then stirred at the temperature and pressure given in the Table ofExample 47 (Methods 1-178) for a period of time also indicated in theTable of Example 47 (Methods 1-178).

Spectrocopic data: 1H NMR (DMSO). 9-b (R1=Boc, R6=Me, R7=Me): 7.66 (m,4H), 7.47 (t, J=7.8, 2H); 7.39-7.26 (m, 3H); 4.25 (m, 1H); 3.04 (dd,J=3.7, 13.1, 1H); 2.91 (m, 1H); 2.6 (m, 1H); 2.46 (dd, J=4.1, 12.2, 1H);2.27 (m, 1H); 2.08 (s, 6H); 1.95 (m, 1H); 1.78 (m, 1H); 1.51 (s, 9H).9-c (R1=Boc, R6=Me, R7=Me) separable signals at 1.51, 1.62, 2.08, 2.17,3.28 ppm.

Case 52466A

Table of Example 47 (Methods 1-178): 9-b (R1 = Boc, Initial R6 = R7 =Amount of Concentration Me):9-c Hetereogeneous Catalyst of 7-a (R1 =Boc) Eqivalents of Temperature Pressure Time (R1 = Boc, Method Catalyst(% w/w) Solvent (mol dm⁻³) Additive Additive (° C.) (bar) (h) R6 = R7 =Me) 1 5% Pd/C 25 THF 0.05 — — 45 5 3 63:37 type 37 2 5% Pd(S)/C 25 THF0.167 — — 40 20 6 51:49 A103038 3 5% Pd(S)/C 25 THF 0.167 — — 40 20 1.553:47 A103038 4 5% Pd/C 25 EtOAc 0.05 — — 40 10 16 53:47 A401102 5 5%Pt/C 25 THF 0.05 — — 40 10 16 65:35 B104032 6 5% Pd/C 25 THF 0.05 — — 4020 16 55:45 A401102 7 5% Pd/C 25 MeOH 0.05 — — 45 5 3 67:33 type 37 8 5%Pd/Al₂O₃ 50 THF 0.05 Cs₂CO₃ 1 40 3 2 36:64 A302084-5 9 5% Pd/C 50 EtOAc0.05 — — 25 3 4 67:33 A109047 10 5% Pd/C 25 THF 0.05 — — 55 3 16 55:45A401102 11 5% Pd/C 25 THF 0.05 — 1 55 10 16 48:52 A401102 12 5% Pd/C 10THF 0.25 — — 70 20 3 57:43 type 37 13 5% Pd/C 25 THF 0.05 — — 40 3 1657:43 A401102 14 5% Pd/C 10 THF 0.25 — — 70 20 3 58:42 type 37 15 5%Pd/C 50 iPrOH 0.05 — — 25 3 4 75:25 A109047 16 5% Pd/C 25 THF 0.167 — —60 20 1.5 61:39 type 37 17 5% Pd(S)/C 25 THF 0.05 — — 40 20 3 54:46A103038 18 5% Pd/C 25 THF 0.25 — — 75 20 1.3 58:42 type 37 19 5% Pd/C 10EtOH 0.05 — — 40 10 16 53:47 A401102 20 5% Pd/C 25 THF 0.05 K₂CO₃ 2 4010 16 62:38 A401102 21 5% Pd/C 50 EtOH 0.05 — — 25 3 4 60:40 A109047 225% Pd/C 25 THF 0.05 — — 45 20 3 64:36 type 37 23 5% Pd/Al₂O₃ 50 EtOH0.05 — — 25 3 4 75:25 A302084-5 24 5% Pt/C 25 THF 0.05 — — 40 10 1667:33 B103018 25 5% Pd/C 25 i-PrOAc 0.25 — — 65 20 3 50:50 type 37 26 5%Pd/C 25 THF 0.05 — — 40 10 16 52:48 A401102 27 5% Pd/C 25 THF 0.05 — —45 5 3 64:36 type 39 28 5% Pt/C 25 THF 0.05 — — 45 5 3 60:40 B501018 295% Pt/C 25 THF 0.05 — — 40 10 16 66:34 B 501032 30 5% Pd/C 40 THF 0.25 —— 75 20 1.3 64:36 type 37 31 5% Pd/C 10 THF 0.05 — — 40 10 16 62:38 type37 32 5% Pd/C 25 EtOH 0.05 — — 40 10 16 59:41 A401102 33 5% Pt/C 25 MeOH0.05 — — 45 5 3 67:33 B501018 34 5% Pd/C 25 THF 0.05 — — 75 5 3 67:33type 37 35 5% Pd/C 25 THF 0.25 — — 65 20 3 62:38 type 39 36 5% Pd/C 10THF 0.05 — — 40 10 16 49:51 type 398 37 5% 25 THF 0.05 — — 40 10 1644:56 Pd/SiO₂/Al₂O₃ C7079 38 5% Pd/C 25 THF 0.05 — — 60 20 3 61:39 type37 39 5% Pd/C 25 Me-THF 0.25 — — 75 20 1.5 57:43 type 37 40 5% Pd/CaCO₃10 THF 0.05 — — 40 10 16 50:50 type 405 41 5% Pd/C 25 THF 0.25 — — 65 204.5 73:27 type 37 42 5% Pd/CaCO₃ 25 THF 0.05 — — 40 10 16 55:45 A30306043 5% Pd/C 25 THF 0.05 — — 45 20 3 64:36 type 39 44 5% Pd/C 27 THF 0.25— — 75 20 2 61:39 type 37 45 5% Pd/C 25 THF 0.05 — — 40 10 16 53:47A401102 46 5% Pd/C 25 EtOH 0.05 — — 25 10 16 54:46 A401102 47 5% Pd/C 25THF 0.05 — — 25 3 16 53:47 A401102 48 5% Pd(S)/C 10 THF 0.05 — — 40 1016 52:48 A103038 49 5% Pd/C 25 THF 0.25 — — 65 20 1.5 63:37 type 37 505% Pd/C 25 THF 0.05 Cs₂CO₃ 1 40 10 16 45:55 A401102 51 5% Pd/C 50 THF0.05 — — 25 3 4 67:33 A109047 52 5% Pd/C 25 THF 0.25 — — 65 20 3 63:37type 37 53 5% Pd/C 10 THF 0.05 — — 40 10 16 50:50 A102023 54 5% Pd/Al₂O₃50 THF 0.05 — — 25 3 4 60:40 A302084-5 55 5% Pd/C 10 THF 0.05 — — 40 1016 48:52 A405032 56 5% Pt/C 25 THF 0.05 — — 40 10 16 61:39 B501018 57 5%Pt/C 25 THF 0.05 Et₃N 1 40 20 3 50:50 B501018 58 5% Pd/C 25 i-PrOAc 0.25— — 65 20 3 52:48 type 37 59 5% Pd/C 25 i-PrOAc 0.25 — — 65 20 3 58:42type 37 60 5% Pd/C 25 Me-THF 0.25 — — 65 20 3 66:34 type 37 61 5%Pd/Al₂O₃ 25 THF 0.05 — — 40 10 16 38:62 A302011 62 5% Pd/C 25 THF 0.05 —— 75 20 3 65:35 type 37 63 5% Pd/C 25 THF 0.05 — — 55 20 16 53:47A401102 64 5% Pd/C 25 THF 0.05 — — 40 10 16 52:48 A405028 65 5% Pd/C 25THF 0.05 — — 60 20 3 63:38 type 39 66 5% Pd/C 10 THF 0.05 — — 75 20 357:43 type 37 67 5% Pd/C 25 THF 0.05 — — 40 10 16 52:48 A102023 68 5%Pd/C 27 THF 0.25 — — 75 20 2.5 64:36 type 37 69 5% Pd/Al₂O₃ 50 THF/H₂O(9:1) 0.05 — — 25 3 4 60:40 A302084-5 70 5% Pd/C 25 THF 0.167 — — 60 203 61:39 type 37 71 5% Pd/C 50 EtOH 0.05 — — 25 3 4 82:18 A405028 72 5%Pd/C 25 THF 0.167 — — 45 20 3 59:41 type 37 73 5% Pd/C 25 THF 0.167 — —45 20 1.5 61:39 type 37 74 5% Pd(S)/C 25 THF 0.05 Et₃N 1 40 20 3 48:52A103038 75 5% Pd/C 10 THF 0.05 — — 40 10 16 57:43 type 394 76 5% Pd/C 25THF 0.05 Et₃N 1 40 20 3 45:55 A102023 77 5% Pd/C 10 HF 0.05 — — 40 10 1651:49 A503038 78 5% Pd/C 25 Me-THF 0.25 — — 65 20 3 63:37 type 39 79 5%Pd/C 25 THF 0.25 — — 65 20 1.5 56:44 type 37 80 5% Pd/C 25 THF 0.167 — —45 20 6 60:40 type 37 81 5% Pd/C 15 THF 0.25 — — 65 20 4 60:40 type 3782 5% Pd/C 15 THF 0.25 — — 65 20 1.5 60:40 type 37 83 5% Pd/C 25 THF0.05 — — 60 20 3 61:39 type 37 84 5% Pd/C 15 THF 0.25 — — 75 20 1.357:43 type 37 85 5% Pd/C 25 THF 0.05 — — 40 10 16 52:48 A405038 86 5%Pd/C 25 THF 0.05 — — 40 10 16 45:55 A102038 87 5% Pd/C 15 THF 0.25 — —75 20 1.3 56:44 type 37 88 5% Pd/C 25 THF 0.05 — — 40 10 16 48:52A405032 89 5% Pd/C 27 THF 0.25 — — 75 20 1.3 58:42 type 37 90 5% 25 THF0.05 — — 40 10 16 50:50 Pd(Pb)/CaCO₃ A 305060 91 5% Pd(S)/C 25 THF 0.167— — 40 20 7.5 51:49 A103038 92 5% Pd(S)/C 25 THF 0.167 — — 40 20 7280:20 A103038 93 5% Pd/C 10 THF 0.05 — — 40 10 16 45:55 type 487 94 5%Pd/C 25 THF 0.05 — — 60 20 3 62:38 type 37 95 5% Pd/C 25 THF 0.25 — — 6520 3 59:41 type 39 96 5% Pd(S)/C 25 THF 0.05 — — 55 20 3 45:55 A10303897 5% Pd/C 25 THF 0.25 — — 65 20 4.5 72:28 type 37 98 5% Pd/C 25 THF0.05 — — 40 10 16 53:47 A503038 99 10% Pd/C 10 THF 0.05 — — 40 10 1658:42 type 394 100 5% 25 THF 0.05 — — 40 10 16 46:54 Pd/SiO₂/Al₂O₃ C7078101 5% Pd/C 25 EtOAc 0.25 — — 65 20 3 61:39 type 37 102 5% Pd/C 25 THF0.05 — — 75 20 3 63:37 type 37 103 5% Pd/C 25 iPrOH 0.05 — — 40 10 1660:40 A401102 104 5% Pt/C 25 THF 0.05 — — 30 20 3 60:40 B501018 105 5%Pd/C 15 THF 0.25 — — 75 20 1.3 58:42 type 37 106 5% Pd/C 25 THF 0.05 — —55 10 16 56:44 A401102 107 5% Pd/C 25 THF 0.25 — — 65 20 1.5 56:44 type37 108 5% Pd/C 10 THF 0.05 — — 40 10 16 48:52 A405038 109 5% Pd/C 10 THF0.05 — — 40 10 16 50:50 A401102 110 5% Pd/C 15 THF 0.05 — — 40 10 1653:47 A401102 111 5% Pt/C 25 MeOH 0.05 — — 45 20 3 71:29 B501018 112 5%Pd/C 25 THF 0.05 — — 60 30 3 61:39 type 37 113 5% Pd/C 15 THF 0.167 — —30 20 16 62:38 type 37 114 5% Pd/C 25 MeOH 0.05 — — 45 5 3 63:37 type 39115 5% Pd/C 25 THF 0.25 — — 75 20 1.3 57:43 type 37 116 5% Pd//TiO₂ 25THF 0.05 — — 40 10 16 49:51 C6944 117 5% Pd/Al₂O₃ 50 THF 0.05 — — 40 3 244:56 A302084-5 118 5% Pd/C 10 THF 0.05 — — 40 10 16 47:53 A109047 1195% Pt/C 25 THF 0.05 — — 40 10 16 68:32 B103014 120 5% Pd/C 25 iPrOH 0.05K₂CO₃ 1 40 10 16 54:46 A401102 121 5% Pd/C 25 THF 0.05 — — 40 10 1662:38 type 37 122 5% Pt/C 25 THF 0.05 — — 40 10 16 66:34 B103032 123 5%Pt/C 25 THF 0.05 — — 40 10 16 63:37 B109032 124 5% Pd/C 25 THF 0.167 — —30 20 72 69:31 type 37 125 5% Pd/C 50 THF 0.05 — — 40 3 2 57:43A401102-5 126 5% Pd(S)/C 25 THF 0.05 — — 40 10 16 50:50 A103038 127 5%Pd/C 50 EtOAc 0.05 — — 25 3 4 69:31 A405028 128 5% Pd/BaSO₄ 25 THF 0.05— — 40 10 16 54:46 A308053 129 5% Pd/ZrO₂ 25 THF 0.05 — — 40 10 16 54:46C7140 130 5% Pd(S)/C 25 THF 0.05 — — 40 20 3 53:47 A103038 131 5% Pd/C50 iPrOH 0.05 — — 25 3 4 64:36 A405028 132 5% Pd/C 25 THF 0.05 — — 40 1016 53:47 A102023 133 5% Pd/C 10 THF 0.05 — — 40 10 16 50:50 A405028 1345% Pd/C 25 MeOH 0.05 — — 45 20 3 65:35 type 37 135 5% Pd/C 10 THF 0.05 —— 40 10 16 55:45 A401102 136 5% Pd(S)/C 25 THF 0.167 — — 40 20 3 53:47A103038 137 5% Pd/C 15 THF 0.25 — — 75 20 1.3 58:42 type 37 138 5% Pd/C25 THF 0.05 — — 40 10 16 50:50 A503032 139 5% Pd/C 10 THF 0.05 — — 40 1016 62:38 type 39 140 5% Pd/C 25 THF 0.05 — — 40 10 16 57:43 type 5R394141 5% Pd/C 25 THF 0.167 — — 60 20 4.5 62:38 type 37 142 5% Pd/C 50 THF0.05 — — 25 3 4 67:33 A405028 143 3% Pd/C 10 THF 0.05 — — 40 10 16 75:25type 39 144 5% Pd/C 25 THF 0.05 — — 40 10 16 60:40 type 39 145 5% Pd/C10 THF 0.05 — — 40 10 16 44:56 type 374 146 5% Pd/C 25 THF 0.05 Cs₂CO₃ 140 10 16 54:46 A401102 147 5% Pd/C 25 THF 0.05 — — 25 10 16 42:58A401102 148 5% Pt(S)/C 25 THF 0.05 — — 40 10 16 64:36 B106032 149 5%Pd/C 10 THF 0.25 — — 70 20 1 57:43 type 37 150 5% Pd/C 25 THF 0.05 — —60 5 3 60:40 type 37 151 5% Pd/C 25 THF 0.05 — — 40 20 3 50:50 A102023152 5% Pt/C 25 THF 0.05 — — 45 20 3 61:39 B501018 153 5% Pd/C 25 THF0.05 — — 40 10 16 59:41 type 5R338 154 5% Pd/C 10 THF 0.25 — — 70 20 160:40 type 37 155 5% Pd/C 25 THF 0.05 — — 25 20 16 58:42 A401102 156 1%Pd/C 10 THF 0.05 — — 40 10 16 74:26 type 39 157 5% Pd/C 10 THF 0.05 — —40 10 16 49:51 A503023 158 5% Pd/C 25 THF 0.05 — — 60 5 3 62:38 type 39159 5% Pd/C 25 THF 0.167 — — 45 20 4.5 59:41 type 37 160 5% Pd(S)/C 25THF 0.05 Et₃N 1 40 20 3 53:47 A103038 161 5% Pd/C 25 EtOH 0.05 — — 40 316 57:43 A401102 162 5% Pd/C 10 THF 0.05 — — 40 10 16 44:56 type 87L 1635% Pd/C 25 MeOH 0.05 — — 45 20 3 62:38 type 39 164 5% Pd/C 15 THF 0.25 —— 65 20 3 60:40 type 37 165 5% Pd/C 25 THF 0.05 K₂CO₃ 1 40 10 16 58:42A401102 166 5% Pd/C 50 Toluene 0.05 — — 25 3 4 73:27 A405028 167 10%Pd/C 7.5 THF 0.25 — — 75 20 1.3 55:45 type 37 168 5% Pd/Al₂O₃ 50 iPrOH0.05 — — 25 3 4 63:38 A302084-5 169 5% Pd/C 25 THF 0.25 — — 65 20 1.562:38 type 37 170 5% Pd/C 25 THF 0.25 — — 65 20 3 64:36 type 37 171 5%Pt/C 25 THF 0.05 — — 40 20 3 61:39 B501018 172 5% Pd/Al₂O₃ 50 EtOH 0.05— — 40 3 2 33:67 A302084-5 173 5% Pd/C 25 THF 0.25 — — 75 20 0.5 58:42type 37 174 5% Pd/C 25 EtOH 0.05 — — 25 3 16 50:50 A401102 175 5% Pd/C25 THF 0.05 — — 40 10 16 52:48 A503023 176 5% Pd(S)/C 25 THF 0.05 — — 4010 16 51:49 A103038 177 5% Pd/C 25 THF 0.05 — — 40 10 16 46:54 A109047178 5% Pd/C 10 THF 0.05 — — 40 10 16 50:50 A503032

HPLC Method (Example 47, Methods 1-178)

Column: X-BRIDGE; 75×4.6 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%) inwater); Mobile Phase B (Acetonitrile). Gradient: 0 min (40% B); 1 min(40% B); 15 min (70% B); 18 min (70% B); 19 min (40% B); 20 min (40% B).Flow rate: 1 ml min¹. Wavelength: 254 nm. Column temperature: 10° C.

Retention times

9-b (R1=Boc, R6=Me, R7=Me): 9.4 min 9-c (R1=Boc, R6=Me, R7=Me): 10.4 min7-a (R1=Boc): 11.5 min 4-a (R1=Boc): 14.1 min 3-a (R1=Boc) and 3-b(R1=Boc): 14.9 min Example 48 (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc)

The residue obtained from Example 69 containing(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc),(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc) and (3R/S,5S)-5-biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc) is purified by columnchromatography, eluting with ethyl acetate-heptane (1:1) to give (3R/S,5S)-5-biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc) as a 62:38 mixture of(3S,5S):(3R,5S) diastereoisomers, respectively, as determined by NMR. 1HNMR (DMSO): 1.49-1.51, 1.67-1.72, 1.81-1.85, 1.93-2.04, 2.56-2.63,2.72-2.77, 2.81-2.85, 3.03-3.06, 3.28-3.32, 3.46-3.52, 3.57-3.63,4.17-4.27, 4.72-4.74, 4.94-4.96, 7.30-7.36, 7.43-7.46, 7.62-7.66.

Example 49(3R/S,5S)-5-Biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (11-a, R1=Boc, R4=Tosyl)

Method 1

20 mg (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc) (prepared according to Example 48)is added to chloroform (5 ml) at room temperature. Triethylamine (11 μl)is added to the mixture. 4-Toluenesulphonic acid anhydride (20.5 mg) isthen added to the mixture. The mixture is then stirred for 20 h at roomtemperature. The volatiles are removed under reduced pressure and theresulting crude material is purified by column chromatography, elutingwith heptane-ethyl acetate (2:1) to afford(3R/S,5S)-5-biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (11-a, R1=Boc, R4=Tosyl) as a 69:31 mixture ofdiastereoisomers as determined by NMR. 1H NMR (CDCl₃): 1.51-1.53,1.67-1.80, 2.08-2.17, 2.36, 2.64-2.79, 3.01 and 3.33, 3.89-4.16,4.20-4.36, 7.15-7.69.

Method 2

100 mg (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc) (prepared according to Example 48)is added to chloroform (3 ml) at room temperature. Triethylamine (110μl) is added to the mixture. 4-Toluenesulphonic acid anhydride (128 mg)is then added to the mixture. The mixture is then stirred for 20 h atroom temperature. Ethyl acetate (2 ml) is added to the mixture.

The mixture is washed with saturated sodium hydrogen carbonate solution(2×1 ml). The organic phase is dried (MgSO₄) and concentrated underreduced pressure. Purification by column chromatography, eluting withheptane-ethyl acetate (2:1) affords(3R/S,5S)-5-biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (11-a, R1=Boc, R4=Tosyl). LC-MS (+ES): 480([MH—C₄H₈]⁺, 100%), 553 ([MNH₄]⁺, 55), 1088 ([2M+NH₄]⁺, 20).

Example 50Potassium[(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester]hexafluorophosphate (7-a, R1=Boc, R6=Me, R7=Me)

Potassium tert-butoxide solution (16 ml, 0.5 M in tetrahydrofuran) isadded to 2.46 g N,N,N′,N′-tetramethylformamidinium hexafluorophosphate(18, R6=Me, R7=Me) (prepared according to Example 3). The resultingmixture is heated to 60° C. and stirred at this temperature for 1 h. Theresulting mixture is cooled to ambient temperature. 1 g(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) is added to the mixture. The resulting mixture isstirred for 20 h at ambient temperature. The mixture is then dilutedwith water (20 ml) and toluene (20 ml). The phases are then separated.The organic phase is washed with saturated sodium carbonate solution(2×20 ml) and then with brine (20 ml). The organic phase is dried(MgSO₄) and concentrated under reduced pressure. The residue is purifiedby column chromatography, eluting with 40% ethyl acetate in hexane.Diethyl ether is added to the residue after concentration and theresulting solid is collected by filtration and dried. 1H NMR (CDCl₃):1.57-1.59, 2.57-2.63, 2.68-2.71, 2.79-2.84, 3.00, 3.24-3.28, 4.30-4.34,7.17, 7.30-7.60. 19F NMR (CDCl₃): -74.9 ppm.

The X-ray Structure of the obtained crystals is shown in FIG. 6. Singlecrystal for this determination is obtained from tert-butylmethylether assolvent.

Crystal Data [Recorded at 120(2) K]

Empirical formula C_(27.5)H₃₆F₃K_(0.5)N₂O_(3.5)P_(0.5) Formula weight542.62 Crystal system Triclinic Space group P1 Cell parameters a =15.089(9) Å b = 17.068(10) Å c = 18.798(12) Å α = 88.79(4)° β =67.67(3)° γ = 72.63(4)° Volume of unit cell 4251(4) Å³ Z^(*) 6Calculated density 1.272 mg m⁻³ ^(*)(number of asymmetric units in theunit cell)

Example 51(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me)

General Procedure for Methods 1-35

(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (amount in mmol given in the Table of Example 51(Methods 1-35)) is added to an ionic salt (identity and amount given inthe Table of Example 51 (Methods 1-35)). Optionally, a solvent (volumeand identity given in the Table of Example 51 (Methods 1-35)) is added.Bredereck's reagent [Tris(dimethylamino)methane (13, R6=Me, R7=Me),Tert-Butoxy-bis(dimethylamino)methane (14, R6=Me, R7=Me, R8=tBu) andN,N-Dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu)](volume given in the Table of Example 51 (Methods 1-35)). The mixture isthen stirred at ambient temperature for 3 h to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Table of Example 51 (Methods 1-35): Total Volume [13, 14 8-a (R1 = Boc)and 15 (R6 = Me, R7 = Equivalents of Volume of Method (mmol) Me, R8 =tBu)] (ml) Ionic Salt ionic salt Solvent solvent (ml) 1 2 4 KPF₆ 1 — 2 24 NH₄PF₆ 1 — 3 2 4 1-Butyl-3-methyl imidazolium PF₅ 1 — 4 2 41-Butyl-3-methyl imidazolium BF₄ 1 — 5 2 4 NaCl 1 — 6 2 4 KCl 1 — 7 2 4KClO₄ 1 — 8 2 4 NaPF₆ 1 — 9 2 4 LiPF₆ 1 — 10 2 4 LiCl 1 — 11 2 4 LiBr 1— 12 2 4 Na₂SiF₆ 1 — 13 1 2 LiNH₂ 1 — 14 1 2 Li₂CO₃ 1 — 15 1 2 KPF₆ 1 —16 1 1 KPF₆ 1 THF 1 17 1 2 KPF₆ 0.5 — 18 1 2 KPF₆ 0.1 — 19 1 2 LiPF₆ 1 —20 1 1 LiPF₆ 1 THF 1 21 1 0.6 LiPF₆ 1 THF 1.4 22 1 0.4 LiPF₆ 1 THF 1.623 1 0.3 LiPF₆ 1 THF 1.7 24 1 1 LiPF₆ 0.2 THF 1 25 1 0.6 LiPF₆ 0.2 THF1.4 26 1 0.3 LiPF₆ 0.2 THF 1.7 27 1 2 LiCl 1 — 28 1 2 LiCl 1 — 29 1 1LiCl 1 THF 1 30 1 0.6 LiCl 1 THF 1.4 31 1 0.4 LiCl 1 THF 1.6 32 1 2 LiCl0.2 — 33 1 1 LiCl 0.2 THF 1 34 1 0.6 LiCl 0.2 THF 1.4 35 1 0.4 LiCl 0.2THF 1.6

Method 36

(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (2 mmol) is added to potassium hexafluorophosphate(1 eq) and 18-crown-6 (1 eq). Bredereck's reagent[Tris(dimethylamino)methane (13, R6=Me, R7=Me),Tert-Butoxy-bis(dimethylamino)methane (14, R6=Me, R7=Me, R8=tBu) andN,N-Dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu)](4 ml) is added. The mixture is then stirred at ambient temperature for3 h to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Example 52(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me)

Method 1

A mixture of lithium tert-butoxide (2.8 eq, 2.8 mmol, 1 M solution inTHF) and N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18,R6=Me, R7=Me) (3 eq, 3 mmol) is stirred at 60° C. for 1 h. The mixtureis then cooled to room temperature. The mixture is then diluted withtetrahydrofuran to a total volume of 5 ml.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (1 eq, 1 mmol) is then added to the mixture. Themixture is then stirred at room temperature for 3 h. The volatiles areremoved under reduced pressure. Ethyl acetate (20 ml) is added to themixture. The phases are separated and the organic phase washed withsaturated sodium carbonate solution (2×20 ml) and brine (20 ml). Theorganic phase is dried (Na₂SO₄) and concentrated under reduced pressureto afford(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Method 2

A mixture of lithium tert-butoxide (2.8 eq, 2.8 mmol, 1 M solution inTHF) and N,N,N′N′-tetramethylformamidinium chloride (18, R6=Me, R7=Me)(3 eq, 3 mmol) are stirred at 60° C. for 1 h. The mixture is then cooledto room temperature. The mixture is then diluted with tetrahydrofuran toa total volume of 5 ml.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (1 eq, 1 mmol) is then added to the mixture. Themixture is then stirred at room temperature for 3 h. The volatiles areremoved under reduced pressure. Ethyl acetate (20 ml) is added to themixture. The phases are separated and the organic phase is washed withsaturated sodium carbonate solution (2×20 ml) and brine (20 ml). Theorganic phase is dried (Na₂SO₄) and concentrated under reduced pressureto afford(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Method 3

A mixture of potassium tert-butoxide (2.8 eq, 2.8 mmol, 1 M solution inTHF) and N,N,N′N′-tetramethylformamidinium chloride (18, R6=Me, R7=Me)(3 eq, 3 mmol) are stirred at 60° C. for 1 h. The mixture is then cooledto room temperature. The mixture is then diluted with tetrahydrofuran toa total volume of 5 ml.(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (1 eq, 1 mmol) and lithium chloride (1 eq, 1 mmol)is then added to the mixture. The mixture is then stirred at roomtemperature for 3 h. The volatiles are removed under reduced pressure.Ethyl acetate (20 ml) is added to the mixture. The phases are separatedand the organic phase washed with saturated sodium carbonate solution(2×20 ml) and brine (20 ml). The organic phase is dried (Na₂SO₄) andconcentrated under reduced pressure to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(E) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Example 53(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me)

Method 1

351 mg (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) (1 eq, 1 mmol) and lithiumhexafluorophosphate (1 eq) is added to tetrahydrofuran (10 ml).N,N-Dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu) (3eq) and dimethylamine (0.5 eq) are added to the mixture. The mixture isstirred at room temperature for 3 h. The volatiles are removed underreduced pressure. Ethyl acetate (20 ml) is then added. The mixture iswashed with saturated sodium carbonate solution (2×20 ml) and then withbrine (20 ml). The organic layer is dried (Na₂SO₄) and concentratedunder reduced pressure to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

General Procedure for Methods 2-6

351 mg (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) (1 eq, 1 mmol) and lithiumhexafluorophosphate (1 eq) is added to tetrahydrofuran (10 ml).Tris(dimethylamino)methane (13, R6=Me, R7=Me) (1.5 eq, 2 eq or 3 eq) andN,N-Dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu),diisopropylamine or diphenylamine (1 eq, 1.5 eq, 3 eq or 4 eq) are addedto the mixture. The mixture is stirred at room temperature for 3 h. Thevolatiles are removed under reduced pressure. Ethyl acetate (20 ml) isthen added. The mixture is washed with saturated sodium carbonatesolution (2×20 ml) and then with brine (20 ml). The organic layer isdried (Na₂SO₄) and concentrated under reduced pressure to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Method 2

Tris(dimethylamino)methane (13, R6=Me, R7=Me) (1.5 eq);N,N-Dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu)(1.5 eq)

Method 3

Tris(dimethylamino)methane (13, R6=Me, R7=Me) (3 eq); diisopropylamine(3 eq)

Method 4

Tris(dimethylamino)methane (13, R6=Me, R7=Me) (3 eq); Diphenylamine (3eq)

Method 5

Tris(dimethylamino)methane (13, R6=Me, R7=Me) (2 eq); Diphenylamine (4eq)

Method 6

Tris(dimethylamino)methane (13, R6=Me, R7=Me) (3 eq); Diphenylamine (1eq)

Example 54(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me)

General Procedure for Methods 1-8

351 mg (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (8-a, R1=Boc) and N,N,N′N′-tetramethylformamidiniumhexafluorophosphate (18, R6=Me, R7=Me) (0.1 or 1 eq) are dissolved in 10ml of a solvent (tetrahydrofuran, 1 dioxane in tetrahydrofuran, 5%dioxane in tetrahydrofuran, 20% dioxane in tetrahydrofuran, dioxane ortetrahydrofuran containing 50 mol %N,N,N′N′-tetramethylethylenediamine). 520 μl Tris(dimethylamino)methane(13, R6=Me, R7=Me) is added to the mixture. Tertiary butanol (1 eq or 3eq) is then added to the mixture. The resulting mixture is stirred atambient temperature for 3 h. The volatiles are then removed underreduced pressure. Ethyl acetate (20 ml) is added to the mixture. Themixture is then washed with saturated sodium carbonate solution (2×20ml) and then with brine. The organic phase is dried (Na₂SO₄) andconcentrated under reduced pressure to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Method 1

N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me): 1 eq; Tertiary butanol (3 eq); Solvent: Tetrahydrofuran

Method 2

N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me): 1 eq; Tertiary butanol (1 eq); Solvent: Tetrahydrofuran

Method 3

N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me): 0.1 eq; tertiary butanol (1 eq); Solvent: 1 Dioxane inTetrahydrofuran

Method 4

N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me): 0.1 eq; tertiary butanol (1 eq); Solvent: 5% Dioxane inTetrahydrofuran

Method 5

N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me): 0.1 eq; tertiary butanol (1 eq); Solvent: 10% Dioxane inTetrahydrofuran

Method 6

N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me): 0.1 eq; tertiary butanol (1 eq); Solvent: 20% Dioxane inTetrahydrofuran

Method 7

N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me): 0.1 eq; tertiary butanol (1 eq); Solvent: Dioxane

Method 8

N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me,R7=Me): 0.1 eq; tertiary butanol (3 eq); Solvent: Tetrahydrofurancontaining 50 mol % N,N,N′N′-tetramethylethylenediamine

Example 55(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me)

General Procedure for Methods 1-3

351 mg (1 mmol) (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (8-a, R1=Boc) and magnesium chloride (0.1, 1 or 2eq) are added to tetrahydrofuran (10 ml). The mixture is stirred at roomtemperature. Tris(dimethylamino)methane (13, R6=Me, R7=Me) (3 eq) andtertiary butanol (3 eq) are added. The mixture is stirred at roomtemperature for 3 h. The volatiles are removed under reduced pressure.Ethyl acetate (2×20 ml) is added. The mixture is washed with saturatedsodium carbonate solution (2×20 ml) and brine (20 ml). The organic phaseis dried (Na₂SO₄) and concentrated under reduced pressure to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Method 1

Magnesium chloride (0.1 eq)

Method 2

Magnesium chloride (1 eq)

Method 3

Magnesium chloride (2 eq)

Example 56(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me)

LHMDS (1 M solution in THF, 2 ml, 2 mmol) is added to a mixture ofdiphenylamine (340 mg, 2 mmol) and N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (492 mg, 2 mmol) in tetrahydrofuran (2 ml). Themixture is then stirred at room temperature for 0.5 h. The mixture isdiluted by addition of tetrahydrofuran (5 ml).(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butylester (8-a, R1=Boc) (351 mg, 1 mmol) is then added to the mixture. Themixture is stirred for 15 min at room temperature. The volatiles areremoved under reduced pressure. Ethyl acetate (20 ml) is added to themixture. The mixture is washed with saturated sodium carbonate solution(2×20 ml) and brine (20 ml). The organic phase is dried (Na₂CO₃) andconcentrated under reduced pressure to afford(R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. Thesolutions are analysed by TLC (50% ethyl acetate in hexane). R_(F) 0.21(salt of 7-a, R1=Boc, R6=Me, R7=Me); R_(F) 0.27 (7-a, R1=Boc, R6=Me,R7=Me); R_(F) 0.68 (8-a, R1=Boc).

Example 57 (S)-1-benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one (8-a,R1=Benzyl)

2.51 g S)-5-Biphenyl-4-ylmethyl-pyrrolidin-2-one (8-a, R1=H) and sodiumhydride (312 mg, 13 mmol) are added to tetrahydrofuran, with stirring.Benzyl bromide (1.43 ml) is added and the resulting mixture stirred for4 h. The volatiles are removed under reduced pressure. Ethyl acetate (50ml) is added to the mixture. The organic phase is washed with saturatedsodium carbonate solution (2×40 ml) and brine (40 ml). The organic phaseis dried (Na₂SO₄) and concentrated under reduced pressure. The residueis purified by column chromatography (60% ethyl acetate in hexane) toafford (S)-1-benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one (8-a,R1=Benzyl). 1H NMR (DMSO): 1.6-1.9 (2H), 2.1 (2H), 2.6 (1H), 3.0 (1H),3.5-3.7 (1H), 4.2 (1H), 4.8 (1H), 7.1-7.7 (14H).

Example 58 Tris(dimethylamino)methane (13, R6=Me, R7=Me),Tert-Butoxy-bis(dimethylamino)methane (14, R6=Me, R7=Me, R8=tBu) andN,N-Dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu)

General Procedure for Methods 1-39

Tris(dimethylamino)methane (13, R6=Me, R7=Me) (0.1 eq or 0.25 eq or 0.5eq or 0.75 eq or 0.9 eq) is added to N,N-Dimethylformamide di-tert-butylacetal (15, R6=Me, R7=Me, R8=tBu) (0.1 eq or 0.25 eq or 0.5 eq or 0.75eq or 0.9 eq) at room temperature. Optionally, potassiumhexafluorophosphate (0 eq or 0.2 eq or 1 eq) is added to the mixture.Optionally, lithium chloride (0 eq or 1 eq) is added to the mixture. Theresulting mixture is then stirred at room temperature or at elevatedtemperature (45° C. or 60° C. or 80° C.) for a given time (1 h or 2 h or4 h or 16 h or 18 h or 21 h) to afford a mixture oftris(dimethylamino)methane (13, R6=Me, R7=Me),tert-butoxy-bis(dimethylimino)methane (14, R6=Me, R7=Me, R8=tBu) andN,N-dimethylformamide di-tert-butyl acetal (15, R6=Me, R7=Me, R8=tBu).Spectroscopic data as in Example 14, Method 1.

Equivalents of Equivalents of Equivalents of 13 Equivalents of 15potassium lithium Temperature Reaction Method (R6 = Me, R7 = Me) (R6 =Me, R7 = Me) hexafluorophosphate chloride (° C.) Time (hours) 1 0.5 0.50 0 rt 16 2 0.5 0.5 1 0 rt 2 3 0.9 0.1 0 0 45 16 4 0.9 0.1 0 0 45 4 50.25 0.75 0 0 45 1 6 0.75 0.25 0 0 45 16 7 0.5 0.5 0 0 80 4 8 0.9 0.1 00 80 16 9 0.1 0.9 0 0 80 4 10 0.25 0.75 0 0 80 1 11 0.5 0.5 0 0 80 1 120.25 0.75 0 0 80 4 13 0.5 0.5 0 0 80 16 14 0.9 0.1 0 0 80 1 15 0.9 0.1 00 45 1 16 0.1 0.9 0 0 45 16 17 0.75 0.25 0 0 45 1 18 0.5 0.5 0 0 rt 1 190.5 0.5 1 0 rt 21 20 0.5 0.5 0 0 45 16 21 0.5 0.5 0 0 45 4 22 0.75 0.250 0 80 4 23 0.75 0.25 0 0 80 16 24 0.1 0.9 0 0 80 16 25 0.1 0.9 0 0 45 426 0.25 0.75 0 0 45 4 27 0.25 0.75 0 0 80 16 28 0.1 0.9 0 0 45 1 29 0.50.5 1 0 rt 18 30 0.75 0.25 0 0 80 1 31 0.5 0.5 0 0 rt 4 32 0.75 0.25 0 045 4 33 0.9 0.1 0 0 80 4 34 0.5 0.5 0 1 60 2 35 0.5 0.5 1 0 60 2 36 0.10.9 0 0 80 1 37 0.5 0.5 0.2 0 60 2 38 0.5 0.5 0 0 45 1 39 0.25 0.75 0 045 16

Example 59(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-a, R1=Boc, R2=H, R3=CO₂Me)

2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) prepared according to Example 2 inWO/2008/031567 is added to 2.55 g caesium carbonate. Dimethylformamide(4 ml) is then added. Methyl iodide (0.55 ml) is then added and themixture is stirred for 16 h at room temperature. Water (10 ml) andisopropyl acetate (10 ml) are added. The phases are separated. Theaqueous phase is washed with isopropyl acetate (2×10 ml). The combinedorganic phases are washed with 20% aqueous sodium chloride solution (15ml) and then dried (MgSO₄). The mixture is concentrated under reducedpressure to afford(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-a, R1=Boc, R2=H, R3=CO₂Me). 1H NMR (CDCl₃): 1.18(3H), 1.41 (9H), 1.51 (1H), 1.95 (1H), 2.66 (1H), 2.85 (2H), 3.70 (3H),3.94 (1H), 4.36 (1H), 7.25 (2H), 7.35 (1H), 7.45 (2H), 7.53 (2H), 7.59(2H).

Example 60(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-a, R1=Boc, R2=H, R3=CO₂Me) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-b, R1=Boc, R2=H, R3=CO₂Me)

2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) and(2S,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H), ratio of diastereomers of 80:20ratio, respectively, prepared according to Example 3 in WO/2008/031567,is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is thenadded. Methyl iodide (0.55 ml) is then added and the mixture is stirredfor 16 h at room temperature. Water (10 ml) and isopropyl acetate (10ml) are added. The phases are separated. The aqueous phase is washedwith isopropyl acetate (2×10 ml). The combined organic phases are washedwith 20% aqueous sodium chloride solution (15 ml) and then dried(MgSO₄). The mixture is concentrated under reduced pressure to afford(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-a, R1=Boc, R2=H, R3=CO₂Me) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-a, R1=Boc, R2=H, R3=CO₂Me) as an 80:20 mixture ofdiastereomers, respectively. 1H NMR (CDCl₃): 1.17-1.20, 1.25-1.26, 1.41,1.46-1.63, 1.76-1.85, 1.92-1.99, 2.51-2.59, 2.61-2.71, 2.76-2.85, 3.70,3.83-3.99, 4.09-4.40, 7.25-7.28, 7.33-7.37, 7.43-7.47, 7.53-7.55,7.59-7.61. Ratio of diastereomers 80:20 (1-a, R1=Boc, R2=H, R3=CO₂Me:1-b, R1=Boc, R2=H, R3=CO₂Me) by integration of signals at 1.76-1.85(1-b, R1=Boc, R2=H, R3=CO₂Me) and 1.92-1.99 (1-a, R1=Boc, R2=H,R3=CO₂Me).

Example 61(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidmethyl ester (2-a, R1=Boc, R2=H, R3=CO₂Me)

30 g (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoicacid (2-a, R1=Boc, R2=H, R3=CO₂H), prepared according to Example 33 isadded to 38.4 g caseium carbonate. Dimethylformamide (50 ml) is thenadded. Methyl iodide (8.26 ml) is then added and the mixture is stirredfor 16 h at room temperature. Water (1200 ml) and isopropyl acetate (120ml) are added. The phases are separated. The aqueous phase is washedwith isopropyl acetate (2×120 ml). The combined organic phases arewashed with 20% aqueous sodium chloride solution (180 ml) and then dried(MgSO₄). The mixture is concentrated under reduced pressure to afford(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidmethyl ester (2-a, R1=Boc, R2=H, R3=CO₂Me). 1H NMR (CDCl₃): 1.40 (9H),2.38 (1H), 2.61 (1H), 2.86 (1H), 2.91 (1H), 3.78 (3H), 4.07 (1H), 4.52(1H), 5.64 (1H), 6.25 (1H), 7.29 (2H), 7.35 (1H), 7.45 (2H), 7.55 (2H),7.59 (2H).

Example 62(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et)

2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) prepared according to Example 2 inWO/2008/031567 is added to 2.55 g caesium carbonate. Dimethylformamide(4 ml) is then added. Ethyl iodide (0.55 ml) is then added and themixture is stirred for 16 h at room temperature. Water (10 ml) andisopropyl acetate (10 ml) are added. The phases are separated. Theaqueous phase is washed with isopropyl acetate (2×10 ml). The combinedorganic phases are washed with 20% aqueous sodium chloride solution (15ml) and then dried (MgSO₄). The mixture is concentrated under reducedpressure to afford(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et). 1H NMR (CDCl₃): 1.18(3H), 1.27 (3H), 1.42 (9H), 1.49 (1H), 1.95 (1H), 2.62 (1H), 2.85 (2H),3.94 (1H), 4.16 (2H), 4.36 (1H), 7.26 (2H), 7.35 (1H), 7.45 (2H), 7.55(2H), 7.59 (2H).

Example 63(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-b, R1=Boc, R2=H, R3=CO₂Et)

2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H) and(2S,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (1-a, R1=Boc, R2=H, R3=CO₂H), ratio of diastereomers of 80:20ratio, respectively, prepared according to Example 3 in WO/2008/031567,is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is thenadded. Ethyl iodide (0.55 ml) is then added and the mixture is stirredfor 16 h at room temperature. Water (10 ml) and isopropyl acetate (10ml) are added. The phases are separated. The aqueous phase is washedwith isopropyl acetate (2×10 ml). The combined organic phases are washedwith 20% aqueous sodium chloride solution (15 ml) and then dried(MgSO₄). The mixture is concentrated under reduced pressure to afford(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et) as an 80:20 mixture ofdiastereomers, respectively. 1H NMR (CDCl₃): 1.16-1.20, 1.25-1.29, 1.42,1.47-1.52, 1.56-1.62, 1.76-1.84, 1.92-1.98, 2.48-2.57, 2.58-2.67,2.77-2.88, 3.77-4.01, 4.10-4.18, 4.32-4.41, 7.26-7.28, 7.33-7.37,7.43-7.47, 7.53-7.55, 7.59-7.60. Ratio of diastereomers 80:20 (1-a,R1=Boc, R2=H, R3=CO₂Et: 1-b, R1=Boc, R2=H, R3=CO₂Et) by integration ofsignals at 1.76-1.84 (1-b, R1=Boc, R2=H, R3=CO₂Et) and 1.92-1.98 (1-a,R1=Boc, R2=H, R3=CO₂Et).

Example 64(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidethyl ester (2-a, R1=Boc, R2=H, R3=CO₂Et)

30 g (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoicacid (2-a, R1=Boc, R2=H, R3=CO₂H), prepared according to Example 33 isadded to 38.4 g caseium carbonate. Dimethylformamide (50 ml) is thenadded. Ethyl iodide (8.26 ml) is then added and the mixture is stirredfor 16 h at room temperature. Water (1200 ml) and isopropyl acetate (120ml) are added. The phases are separated. The aqueous phase is washedwith isopropyl acetate (2×120 ml). The combined organic phases arewashed with 20% aqueous sodium chloride solution (180 ml) and then dried(MgSO₄). The mixture is concentrated under reduced pressure to afford(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoicacid, ethyl ester (2-a, R1=Boc, R2=H, R3=CO₂Et). 1H NMR (CDCl₃): 1.31(3H), 1.40 (9H), 2.37 (1H), 2.59 (1H), 2.84 (1H), 2.93 (1H), 4.06 (1H),4.24 (2H), 4.56 (1H), 5.62 (1H), 6.25 (1H), 7.29 (2H), 7.35 (1H), 7.45(2H), 7.54 (2H), 7.59 (2H).

Example 65(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-b, R1=Boc, R2=H, R3=CO₂Et)

Method 1

409 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidethyl ester (2-a, R1=Boc, R2=H, R3=CO₂Et) is added to ethanol (9 ml) inVessel A. 14.9 mg [Rh(NBD)₂]BF₄ and 39.6 mg(R)-1-[(R)-2-(2′-dicyclohexylphosphinophenyl)-ferrocenyl]ethyldi(bis-(3,5-trifluoromethyl)phenyl)-phosphine(=Walphos SL-WO08-1) are added to ethanol (3 ml) in Vessel B. Thecontents of Vessel B are stirred for 0.5 h at room temperature. Thecontents of Vessel A and Vessel B are then transferred to Vessel C.Vessel C is purged with hydrogen (20 bar) and then pressurised under ahydrogen atmosphere at 20 bar. The mixture is stirred for 16 h. Thevolatiles are removed under reduced pressure. The residue is analysed byhplc to determine the ratio of(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et) to(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-b, R1=Boc, R2=H, R3=CO₂Et). Diastereomer ratio50.2:49.8 (1-a, R1=Boc, R2=H, R3=COEt: 1-b, R1=Boc, R2=H, R3=COEt) asdetermined by hplc.

Method 2

409 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidethyl ester (2-a, R1=Boc, R2=H, R3=CO₂Et) is added to ethanol (9 ml) inVessel A. 17.4 mg [Ru(COD)(CF₃CO₂)₂] and 44.2 mg(αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene(=Mandyphos SL-M004-1) are added to dichloroethane (3 ml) in Vessel B.The contents of Vessel B are stirred for 0.5 h at 50° C. The volatilesare removed from the mixture in Vessel B under reduced pressure. Ethanol(3 ml) is then added to Vessel B. The contents of Vessel A and Vessel Bare then transferred to Vessel C. Vessel C is purged with hydrogen (20bar) and then pressurised under a hydrogen atmosphere at 20 bar. Themixture is stirred for 16 h. The volatiles are removed under reducedpressure. The residue is analysed by hplc to determine the ratio of(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et) to(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-b, R1=Boc, R2=H, R3=CO₂Et). Diastereomer ratio25.5:74.5 (1-a, R1=Boc, R2=H, R3=COEt: 1-b, R1=Boc, R2=H, R3=COEt) asdetermined by hplc.

General Procedure (Example 65, Methods 3-12)

The Organometallic Complex (A) and Chiral Ligand (L) are added to amixture of ethanol (0.041 ml) and dichloroethane (0.135 ml). The ratioof Chiral Ligand per atom of metal within the Organometallic Complexused is 1.20:1. The S/C ratio is 25. The mixture is stirred for 0.5 h.The solvent is then removed.(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid(2-a, R1=Boc, R2=H, R3=CO₂Et) in ethanol or dichloroethane (0.244 ml) isadded to the vessel containing the Organometallic Complex (A) and ChiralLigand (L). Further solvent is added to give the final concentration of2-a (R1=Boc, R2=H, R3=CO₂H) of 84 mM.

Hydrogen gas at 20 bar is the applied to the vessel containing themixture. The mixture is stirred at 20 bar hydrogen pressure and at roomtemperature for 16 hours.

The reaction solutions are analysed by hplc to determine the ratio of(1-a, R1=Boc, R2=H, R3=CO₂Et) and (1-b, R1=Boc, R2=H, R3=CO₂Et).

Method 3

Chiral Ligand {(2S,4S)-2,4-Bis(diphenylphosphino)pentane=(S,S)-BDPP};Organometallic Complex{bis(trifluoroacetoxy)(1,5-cyclooctadiene)ruthenium(II)}; Solvent:Ethanol. Diastereomer ratio 85:15 ((1-a, R1=Boc, R2=H, R3=CO₂Et):(1-b,R1=Boc, R2=H, R3=CO₂Et) as determined by hplc.

Method 4

Chiral Ligand{(R)-1-[(S)-2-Di-tert.-butylphosphino)ferrocenyl]ethyldicyclohexylphosphine=SL-J505-1};Organometallic Complex{bis(trifluoroacetoxy)(1,5-cyclooctadiene)ruthenium(II)}; Solvent:Ethanol. Diastereomer ratio 71:29 ((1-a, R1=Boc, R2=H, R3=CO₂Et): (1-b,R1=Boc, R2=H, R3=CO₂Et) as determined by hplc.

Method 5

Chiral Ligand{(1S)-Diphenylphosphino-2-[(R)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)-methyl]ferrocene=SL-T001-1};Organometallic Complex{bis(trifluoroacetoxy)(1,5-cyclooctadiene)ruthenium(II)}; Solvent:Ethanol. Diastereomer ratio 70:30 ((1-a, R1=Boc, R2=H, R3=CO₂Et): (1-b,R1=Boc, R2=H, R3=CO₂Et) as determined by hplc.

Method 6

Chiral Ligand{(R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5-xylyl)phosphine=SL-J005-1};Organometallic Complex{bis(trifluoroacetoxy)(1,5-cyclooctadiene)ruthenium(II)}; Solvent:Ethanol. Diastereomer ratio 67:33 ((1-a, R1=Boc, R2=H, R3=CO₂Et): (1-b,R1=Boc, R2=H, R3=CO₂Et) as determined by hplc.

Method 7

Chiral Ligand{(S)-(−)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)-bis(diphenylphosphine)=(S)-Ph-MeOBIPHEP=SL-A101-2};Organometallic Complex {[Ir(COD)₂}BArF}; Solvent: Dichloroethane.Diastereomer ratio 63:37 ((1-a, R1=Boc, R2=H, R3=CO₂Et): (1-b, R1=Boc,R2=H, R3=CO₂Et) as determined by hplc.

Method 8

Chiral Ligand{(S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5-xylyl)phosphine=SL-J005-2};Organometallic Complex {bis(norbornadiene)rhodium(I) tetrafluoroborate};Solvent: Ethanol. Diastereomer ratio 58:42 ((1-a, R1=Boc, R2=H,R3=CO₂Et): (1-b, R1=Boc, R2=H, R3=CO₂Et) as determined by hplc.

Method 9

Chiral Ligand{(R)-1-[(R)-2-(2.-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine=SL-WO01-1};Organometallic Complex {bis(norbornadiene)rhodium(I) tetrafluoroborate};Solvent: Ethanol. Diastereomer ratio 31:69 ((1-a, R1=Boc, R2=H,R3=CO₂Et): (1-b, R1=Boc, R2=H, R3=CO₂Et) as determined by hplc.

Method 10

Chiral Ligand{(S)-1-[(S)-2-(2′-Dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-(3,5-trifluoromethyl)phenyl)-phosphine=SL-WO08-2};Organometallic Complex {bis(norbornadiene)rhodium(I) tetrafluoroborate};Solvent: Ethanol. Diastereomer ratio 16:84 ((1-a, R1=Boc, R2=H,R3=CO₂Et):(1-b, R1=Boc, R2=H, R3=CO₂Et) as determined by hplc.

Method 11

Chiral Ligand{(R)-1-[(S)-2-Diphenylphosphino)ferrocenyl]ethyldi-tert.-butylphosphine=SL-J002-1};Organometallic Complex {bis(norbornadiene)rhodium(I) tetrafluoroborate};Solvent: Ethanol. Diastereomer ratio 2:98 ((1-a, R1=Boc, R2=H,R3=CO₂Et): (1-b, R1=Boc, R2=H, R3=CO₂Et) as determined by hplc.

Method 12

Chiral Ligand {(R)-1-[(S)-2-diethylphosphino)ferrocenyl]ethyldi(tert-butyl)-phosphine=SL-J301-1}; Organometallic Complex{bis(norbornadiene)rhodium(I) tetrafluoroborate}; Solvent: Ethanol.Diastereomer ratio 5:95 ((1-a, R1=Boc, R2=H, R3=CO₂Et):(1-b, R1=Boc,R2=H, R3=CO₂Et) as determined by hplc.

HPLC Method (Example 65, Methods 1-12)

Column: Chiralcel OJ-RH; 150×4.6 mm; 5 μm. Mobile Phase A (water);Mobile Phase B (Acetonitrile). Isocratic: 0 min (60% B); 15 min (60% B).Flow rate: 0.8 ml Wavelength 254 nm. Column temperature: 10° C.

Retention times:

1-b (R1=Boc, R2=H, R3=CO₂Et):9.8 min 1-a (R1=Boc, R2=H, R3=CO₂Et):10.8min 2-a (R1=Boc, R2=H, R3=CO₂Et):15.2 min Example 66(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc)

0.05 g of(3R/S,5S)-5-Biphenyl-4-ylmethyl-3-dimethoxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=Me, R9=Me, Y═O) are dissolved in1 ml of acetone under argon. Then 15 mg of water and 40 mg of amberlyst15 are added. The mixture is stirred for 3 days, then filtered andconcentrated in vacuo to afford(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) as determined by hplc.

HPLC Method

Column: X-BRIDGE C18; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%)in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 210 or 254 nm. Temperature 60° C.

Retention times

2-a (R1=Boc, R2=H, R3=CO₂H): 2.3 min 6-a (R1=Boc): 2.5 min 4-a (R1=H):5.6 min 5-a (R1=Boc): 8.3 min 8-a (R1=Boc): 10.3 min 9-b (R1=Boc, R6=Me,R7=Me): 10.4 min 9-c (R1=Boc, R6=Me, R7=Me): 4-a (R1=Boc): 11.9 minExample 67(3R/S,5S)-5-Biphenyl-4-ylmethyl-3-(bis-butylsulfanyl-methyl)-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=nBu, R9=nBu, Y═S)

0.5 g of5-Biphenyl-4-ylmethyl-3-[1-dimethylamino-meth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) are added to 5 ml ofn-butane-1-thiol. After the addition of 0.2 g of p-toluenesulfonic acidthe mixture is stirred for 6 days at 25° C., then heated to 60° C. for16 hours. The mixture is then quenched by addition of 5 ml of an 8%aqueous bicarbonate solution and any remaining n-butane-1-thioldistilled off under reduced pressure at 40° C. The aqueous phase isextracted 3 times with 5 ml ethyl acetate each and the combined organicphase evaporated to dryness at 40° C. under reduced pressure. Theresidue is purified by column chromatography (heptane: ethyl acetate75:25) to afford(3R/S,5S)-5-biphenyl-4-ylmethyl-3-(bis-butylsulfanyl-methyl)-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=nBu, R9=nBu, Y═S). Ratio of C-3diastereomers determined as 70:30 ((3S,5S):(3R,5S) diastereomers,respectively). 1H NMR (CDCl₃): Data for mixture of diastereomers:0.86-0.96 (6H), 1.32-1.47 (4H), 1.50-1.68 (4H), 1.62 (9H), 1.94-2.30(2H), 2.48-2.74 (4H), 2.80-2.89 (2H), 3.10-3.16 (1H), 3.55-3.59 (1H,minor stereoisomer), 4.23-4.31 (1H, minor stereoisomer), 4.30 (1H), 4.38(1H, minor stereoisomer), 4.43-4.47 (1H), 7.27-7.30 (2H), 7.32-7.40(1H), 7.44-7.50 (2H), 7.56-7.65 (4H).

Example 68(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc)

0.101 g (0.19 mmol) of(3R/S,5S)-5-Biphenyl-4-ylmethyl-3-(bis-butylsulfanyl-methyl)-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (16-a, R1=Boc, R9=nBu, R9=nBu, Y═S) are dissolvedin a mixture of 1.6 ml acetonitrile and 0.4 ml water. After addition of0.115 g HgCl₂ and 0.048 g calcium carbonate, the suspension is stirredover night. Diethyl ether (10 ml) and 18% aq. ammonium chloride solution(5 ml) are added to the mixture. The mixture is then filtered and thephases are separated. The organic phase is washed with water and brineand then concentrated under reduced pressure to give(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc). Material analysed by hplc (hplcmethod for Example 66)

Example 69 (3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (3-a, R1=Boc) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc)

0.24 g(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to a mixture of ethylacetate (10.8 ml) and methanol (1.2 ml) at 22° C. 0.1 g of 10% Palladiumon carbon (Engelhard 4505) is added to the mixture along with water (0.3ml). The mixture is flushed with hydrogen and subsequently is stirred at22° C. and 4 bar hydrogen pressure for five days. The mixture is thenfiltered through Cellflock and concentrated under reduced pressure toafford(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-a, R1=Boc),(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (3-b, R1=Boc) and (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc) as determined by hplc. HPLCConditions as given in Example 66 and Example 71.

Example 70 (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc)

99 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc) is added to a mixture of toluene(0.25 ml) and water (0.25 ml) at room temperature. Tetrabutylammoniumbromide (19.7 mg) is then added. The mixture is then cooled to 0° C.Sodium borohydride (20.8 mg) is then added and the resulting mixture isstirred at 0° C. for 1 h. The mixture is then warmed to room temperatureand stirred overnight. Water (10 ml) and toluene (10 ml) are then addedto the mixture. The phases are separated. The organic phase is washedwith water (10 ml), dried (MgSO₄) and concentrated in vacuo to afford(3R/S,5S)-5-biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc) as detected by LC-MS. m/z(+ESI): 266(10%), 282 (2), 310 (20), 326 (100), 366 (15), 382 ([MH⁺], 8). 1H NMR(DMSO): 1.22-1.52, 1.59-1.65, 1.80-1.87, 1.94-2.03, 2.10-2.18,2.57-2.89, 3.02-3.11, 3.15-3.30, 3.34-3.44, 3.46-3.66, 3.67-3.79,3.82-3.93, 4.16-4.38, 4.63-4.69, 4.72-4.77, 4.93-5.00, 5.14-5.27,5.40-5.63, 5.66-5.78, 6.23-6.29, 6.63-6.29, 6.63-6.67, 7.12-7.20,7.23-7.37, 7.43-7.47, 7.55-7.68.

Example 71(R)-5-Biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc)

Method 1

100 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethanol(0.5 ml). 160 mg Cesium carbonate is added to the mixture. 30 mgPalladium on Carbon (10% loading, 50% water wet, Degussa E101 NE/W) isadded to the mixture. Hydrogen gas is applied to the mixture. Themixture is then stirred at ambient temperature and pressure overnight.The catalyst is then filtered and the mixture concentrated under reducedpressure. The residue is analysed by hplc to identify(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc).

Method 2

189 mg(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethanol(0.5 ml). 108 μl 2,6-Lutidine are added to the mixture. 57 mg Palladiumon Carbon (10% loading, 50% water wet, Johnson Matthey type 39) is addedto the mixture. Hydrogen gas is applied to the mixture. The mixture isthen stirred at ambient temperature and pressure overnight. The catalystis then filtered and the mixture concentrated under reduced pressure.The residue is analysed by hplc to identify(R)-5-biphenyl-4-ylmethyl-3-[1-hydroxymeth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6-a, R1=Boc).

HPLC Method 1 (Example 71)

Column: Zorbax Extend C18; 150×4.6 mm; 3.5 μm. Mobile Phase A (0.1% NH₃(32%) in water); Mobile Phase B (Acetonitrile); Mobile Phase C(Methanol). Gradient: 0 min (5% B; 50% C); 1 min (5% B; 50% C); 5 min(5% B; 75% C); 15 min (5% B; 75% C); 15.1 min (5% B; 50% C); 18 min (5%B; 50% C). Flow rate: 1.2 ml Wavelength: 254 nm. Column temperature: 10°C.

Retention times:

6-a (R1=Boc): 4.1 min 9-b (R1=Boc, R6=Me, R7=Me): 9.9 min 9-c (R1=Boc,R6=Me, R7=Me): 10.5 min 4-a (R1=Boc): 11.2 min 7-a (R1=Boc): 11.5 min3-a (R1=Boc): 12.1 min 3-b (R1=Boc): 12.5 min HPLC Method 2 (Example 71)

Column: X-BRIDGE; 150×3.0 mm; 3.5 μm. Mobile Phase A (0.1% NH₃ (32%) inwater); Mobile Phase B (Acetonitrile). Gradient: 0 min (20% B); 3 min(40% B); 5 min (40% B); 7 min (50% B); 11 min (50% B); 13 min (80% B);16 min (80% B); 16.1 min (20% B); 20 min (20% B). Flow rate: 1.4 mlmin⁻¹. Wavelength: 254 nm. Column temperature: 60° C.

Retention times

6-a (R1=Boc): 2.6 min 9-b (R1=Boc, R6=Me, R7=Me): 10.7 min 9-c (R1=Boc,R6=Me, R7=Me): 11.2 min 4-a (R1=Boc): 12.2 min 3-a (R1=Boc) and 3-b(R1=Boc): 12.8 min Example 72(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-b, R1=Boc, R2=H, R3=CO₂Et)

500 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidethyl ester (2-a, R1=Boc, R2=H, R3=CO₂Et) is added to ethanol (5 ml) atambient temperature. Triethylamine (170 μl) is then added to themixture. 50 mg Palladium on carbon (10%, 50% water-wet, Degussa E101NE/W) is then added. Hydrogen gas at ambient pressure is applied to themixture. The mixture is then stirred overnight at ambient temperatureand pressure. The mixture is then filtered and concentrated underreduced pressure to afford2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acidethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Et) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (1-b, R1=Boc, R2=H, R3=CO₂Et). Spectroscopic data as inExample 63. Ratio of diastereomers 70:30 (1-a, R1=Boc, R2=H, R3=CO₂Et:1-b, R1=Boc, R2=H, R3=CO₂Et) as determined by hplc (hplc method as inExample 65)

Example 73(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-a, R1=Boc, R2=H, R3=CO₂Me) and(2S,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-b, R1=Boc, R2=H, R3=CO₂Me)

500 mg(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acidmethyl ester (2-a, R1=Boc, R2=H, R3=CO₂Me) is added to ethanol (5 ml) atambient temperature. Triethylamine (176 μl) is then added to themixture. 50 mg Palladium on carbon (10%, 50% water-wet, Degussa E101NE/W) is then added. Hydrogen gas at ambient pressure is applied to themixture. The mixture is then stirred overnight at ambient temperatureand pressure. The mixture is then filtered and concentrated underreduced pressure to afford2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acidmethyl ester (1-a, R1=Boc, R2=H, R3=CO₂Me) and(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid methyl ester (1-b, R1=Boc, R2=H, R3=CO₂Me). Spectroscopic data asin Example 60. Ratio of diastereomers 66:34 (1-a, R1=Boc, R2=H,R3=CO₂Me: 1-b, R1=Boc, R2=H, R3=CO₂Me) by integration of signals at1.76-1.85 (1-b, R1=Boc, R2=H, R3=CO₂Me) and 1.92-1.99 (1-a, R1=Boc,R2=H, R3=CO₂Me).

Example 74(3R/S,5S)-5-Biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (11-a, R1=Boc, R4=Tosyl) and(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc)

20 mg (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (5-a, R1=Boc) (prepared according to Example 48)is added to chloroform (5 ml) at room temperature. Triethylamine (11 μl)is added to the mixture. 4-Toluenesulphonic acid anhydride (20.5 mg) isthen added to the mixture. The mixture is then stirred for 20 h atreflux. Ethyl acetate (1 ml) and water (1 ml) are added. The phases areseparated. The organic phase is concentrated under reduced pressure. Theresidue is then purified by column chromatography, eluting withheptane-ethyl acetate (1:1) to afford(3R/S,5S)-5-biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (11-a, R1=Boc, R4=Tosyl) and(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data for(3R/S,5S)-5-biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (11-a, R1=Boc, R4=Tosyl) as for Example 49,Method 1. Spectroscopic data for(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc) as for Example 23, Method 1.

Example 75 (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-iodomethyl-pyrrolidin-2-one(12-a, R1=H, R5=I)

122 mg(3R/S,5S)-5-Biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (11-a, R1=Boc, R4=Tosyl) prepared according toExample 49, Method 2 is added to acetonitrile (3 ml). Sodium iodide (105mg) is then added to the mixture. The resulting mixture is heated atreflux overnight. The mixture is then concentrated under reducedpressure. Purification by column chromatography, eluting with ethylacetate-heptane (1:1) gives(3R/S,5S)-5-biphenyl-4-ylmethyl-3-iodomethyl-pyrrolidin-2-one (12-a,R1=H, R5=I). 1H NMR (CDCl₃): 2.13 (2H), 2.69 (2H), 2.82 (1H), 3.28 (1H),3.35 (1H), 3.85 (1H), 5.84 (1H), 7.17 (2H), 7.28 (1H), 7.37 (2H), 7.49(4H).

Example 76(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc)

5 mg (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-iodomethyl-pyrrolidin-2-one(12-a, R1=H, R5=I) is added to toluene (1 ml). 4-(Dimethylamino)pyridine(0.1 mg) and triethylamine (1 μl) are then added to the mixture. Themixture is heated to 70° C. Di-tert-butyl dicarbonate (2 mg) is thenadded to the mixture. The mixture is stirred for 1 h at 70° C. Themixture is concentrated under reduced pressure. Ethyl acetate (1 ml) andwater (1 ml) are added. The phases are separated. The organic phase isconcentrated under reduced pressure to give(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example23, Method 1.

Example 77 (3R,5S)-5-Biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (3-a,R1=H) and (3S,5S)-5-Biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (3-b,R1=H)

4 mg (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-iodomethyl-pyrrolidin-2-one(12-a, R1=H, R5=I) is added to ethanol (1 ml) at ambient temperature.Triethylamine (5 μl) is then added to the mixture. 0.4 mg Palladium oncarbon (10%, 50% water-wet, Degussa E101 NE/W) is then added. Hydrogengas at ambient pressure is applied to the mixture. The mixture is thenstirred overnight at ambient temperature and pressure. The mixture isthen filtered and concentrated under reduced pressure to afford(3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (3-a, R1=H) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (3-b, R1=H. Ratioof diastereomers 22:88 (3-a, R1=H to 3-b, R1=H) as determined by nmr.Spectroscopic data for 3-a (R1=H) as for Example 6 in WO/2008/083967.Spectroscopic data for 3-b (R1=H) as for Example 47 in WO/2008/083967.

1-60. (canceled)
 61. A compound according to formula (2),

or salt thereof, wherein R1 and R2 are, independently of each other,hydrogen or a nitrogen protecting group, and R3 is a carboxyl group oran ester group, preferably having a configuration according to formula(2-a),


62. A compound of formula (4)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,preferably having a configuration according to formula (4-a),


63. A compound of formula (5), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, preferably offormulae (5-a), (5-b) or (5-c), more preferably (5-b),


64. A compound of formula (6), or a tautomer thereof,

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,preferably having a configuration according to formula (6-a),


65. A compound of formula (7), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, preferably having a configuration according toformula (7-a), (7-b) or (7-c), more preferably (7-b),


66. A compound of formula (9-a), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7are, independently, an alkyl group or together are an alkylene group,preferably having a configuration according to formula (9-a) (9-b) or(9-c), more preferably (9-b),


67. A compound of formula (10), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, R6 and R7 are,independently, an alkyl group, an aryl group, an arylalkyl group, acycloalkyl group or together R6 and R7 form a cycle, together with thenitrogen to which they are attached, which cycle may be saturated orunsaturated and may optionally contain one or more heteroatoms, such anitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, such as4 to 7 ring atoms, Z⁻ is a halide (eg iodide, bromide, chloride), analkyl sulphate (eg methyl sulphate) or a sulfonyl ester (eg triflate)and R10 is hydrogen, alkyl or aryl; preferably having a configurationaccording to formula (10-a), (10-b) or (10-c), more preferably (10-b),


8. A compound of formula (11)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting groupand R4 is an OH-activating group, preferably having a configurationaccording to formula (11-a), (11-b) or (11-c), more preferably (11-b),


69. A compound of formula (16)

or salt thereof, wherein R1 is hydrogen or a nitrogen protecting group,Y is O or S and each R9, is, independently, alkyl, aryl, arylalkyl oracetyl. preferably having a configuration according to formula (16-a),


70. Method of preparing a compound according to claim 1 comprisingsynthesising a NEP-inhibitor or a prodrug thereof, such as a NEPinhibitor or prodrug thereof comprising aγ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone 71.The method according to claim 10, wherein the NEP-inhibitor isN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid or a salt or a prodrug thereof.
 72. The method according to claim10, wherein the NEP-inhibitor prodrug isN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof.